LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of xenobiotics II: Studies with isolated perfused rat liver.

1. To elucidate the determining factors for elimination pathways of sulfate and glucuronide metabolites of xenobiotics, a single-pass perfusion of 4-methylumbelliferone (4MU) or p-nitrophenol (pNP) was performed with an isolated rat liver preparation. 2. Without bovine serum albumin in the perfusion system, clearance calculated based on the unbound concentration in the liver clearly showed that the net efflux clearances (CLeff) of sulfates from the sinusoidal membrane were much higher than those of glucuronides and that the biliary excretion clearances (CLb) of glucuronides were approximately two times larger than those of sulfates. 3. The ratios of CLeff to CLb were much higher for sulfates than those for glucuronides. The bile-oriented elimination of glucuronides or sinusoidal efflux-oriented elimination of sulfates was observed even using the perfusate including 3% bovine serum albumin, but the sinusoidal efflux of sulfates was extensively enhanced by bovine serum albumin in the perfusate. The mechanisms behind this stimulatory effect remain to be elucidated. 4. For both compounds, CLb of glucuronide was comparable with CLb of sulfate, meaning that CLb is not responsible for the biliary excretion of glucuronides at extensively higher rate than sulfates. 5. Higher concentration of glucuronides in the liver, partly caused by much lower CLeff of glucuronides than that of sulfates, is likely responsible for the bile-oriented excretion of glucuronides. The extensive sinusoidal efflux of sulfates, leading to the urine-oriented excretion, is attributed to the substantially higher CLeff than CLb. 6. In conclusion, the sinusoidal efflux is an important factor for determining elimination pathways of both sulfates and glucuronides, although further studies are needed to clarify the mechanisms of the sinusoidal efflux.

Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of drugs. I: studies by in vivo constant infusion.

1. The hepatic and renal handling of glucuronides and sulphates of three phenolic compounds, 4-methylumbelliferone (4-MU), p-nitrophenol (pNP) and acetaminophen (APAP), were evaluated pharmacokinetically by in vivo constant infusion experiments in rat. It was shown that the urinary excretion rate at steady-state was larger than the biliary excretion rate for both glucuronides and sulfates, and sulfates, in particular, were extensively excreted into the urine. 2. For each glucuronide, however, biliary excretion clearances (CL(b)) calculated based on the total concentration and unbound concentration in the liver were much larger than the corresponding renal excretion clearances (CL(r)). Even in the case of sulfates, there was not any large difference between CL(r) and CL(b) based on the total and unbound concentration in tissues, which could not explain their extensive urinary excretion. From these results, these excretion clearances were recognized not to reflect necessarily the actual excretion rate obtained. 3. On the other hand, the tissue-to-plasma concentration ratio (K(p)) of both glucuronides and sulfates for every phenolic compound was much higher in the kidney than that in the liver. The results suggested that one of the most important determinants for the preferential excretion of these conjugates into the bile or urine is the extent of disposition of each compound to the liver or kidney. 4. In addition, K(p) of both glucuronides and sulfates in the liver, where these conjugates are mainly formed, was small. The K(p) of sulfates was quite low, suggesting that sulfates generated in the liver were subject to extensive sinusoidal efflux.

A novel cis-acting cysteine-responsive regulatory element of the gene for the high-affinity glutathione transporter of Saccharomyces cerevisiae.

We cloned a DNA fragment from Saccharomyces cerevisiae that complemented the deficiency in high-affinity glutathione transport activity conferred by a gsh11 mutation, and found that the ORF responsible was YJL212c, which had already been designated as OPT1 and HGT1 by others. Northern analysis clearly demonstrated that this ORF, now referred to as OPT1/ HGT1/ GSH11, was induced by sulfur starvation and repressed by adding cysteine to the growth medium. Reporter gene assays showed that a segment spanning the region between positions -371 and -355 was essential for the regulation of this gene. A sequence of 9 nt, CCGCCACAC (from -364 to -356), in this region was shown to be required for protein binding, using an electrophoretic mobility shift assay. Based on these results, we propose that CCGCCACAC comprises the core of a cis-acting element involved in cysteine-responsive gene regulation in S. cerevisiae.

Adjacent-segment morbidity after Graf ligamentoplasty compared with posterolateral lumbar fusion.

OBJECT: Of concern to spine surgeons are accelerated degenerative changes of motion segments located above and below where spinal fusion has been performed. Graf artificial ligament stabilization has been developed to avoid the adverse effect of spinal fusion. The object of this study was to assess the adjacent-segment morbidity of Graf ligamentoplasty compared with posterolateral fusion (PF) in which instrumentation was used. METHODS: Data obtained in 45 patients who underwent L4-5 Graf ligamentoplasty (18 patients) or PF with instrumentation (27 patients) were reviewed retrospectively. The minimum follow-up period was 5 years. In the PF group a solid fusion rate of 92.6% was achieved. Radiographic evaluation included assessment of lumbar sagittal alignment, range of motion (ROM), and adjacent-disc degeneration. Adjacent-segment morbidity was clinically assessed by determining the reoperation rate. Graf ligamentoplasty maintained regional lordosis and flexibility (13 degrees in L4-5 lordosis; 4.4 degrees in L4-5 ROM). Although there was no difference in preoperative adjacent-disc condition between the two groups, radiographic evidence of adjacent-disc deterioration was observed more frequently in patients in the PF group than the Graf group (25% and 6% at L1-2; 38% and 6% at L2-3; 38% and 18% at L3-4; and 43% and 18% at L5-sacrum, respectively). One case in the Graf group (5.6%) and five cases in the PF group (18.5%) required additional surgeries for adjacent-segment lesions. CONCLUSIONS: Graf ligamentoplasty cannot completely replace spinal fusion. In a well-selected group of patients, however, it was shown to maintain lumbar mobility and sagittal alignment, and it decreased the risk of adjacent-segment deterioration compared with PF with instrumentation.

[Assessment by means of a Minimum Data Set of the changes of mental and physical status of elderly patients with dementia during two years of institutionalization].

Using a Minimum Data Set, we studied how the mental and physical conditions of elderly people with dementia changed during two years of institutionalization. Fifty-five patients with dementia of Alzheimer's type (DAT) and 25 with vascular dementia (VD) admitted to the dementia ward in Kyoto Higashiyama Geriatric Hospital were investigated. We assessed them at the time of their institutionalization, and every three months for two years. On institutionalization, a difference between DAT and VD was noted in the group in which more than 10 areas of Resident Assessment Protocols (RAPs) were triggered. The areas of delirium, communication, behavioral problem, activities, activities of daily living, dehydration/fluid maintenance, and psychotropic drugs were evenly triggered in both dementia groups. In the DAT group, however, mood state and dental care were also highly triggered while urinary incontinence, falls and nutritional status were highly triggered in the VD group. Three months later, marked improvements were observed in all of the above areas. However, RAPs areas gradually increased subsequently, and there was marked difference in the areas and their course of progression between the dementia groups. In the DAT group, the trigger rate of the areas of communication, activities of daily living, urinary incontinence, dental care, nutritional status and falls gradually increased after 6 months of evaluation. However, the trigger rate in only three areas, such as communication, visual function and urinary incontinence, become higher, but their patterns of increase were irregular. Mental and physical conditions of the patients with dementia were different in each dementia subtype on institutionalization, but these conditions improved soon after. However, the conditions were gradually became worse, and the pattern was different in each dementia group: DAT showed a slow and steady decline, but VD showed irregular progression and differed among individuals.

Kinematic evaluation of atlantoaxial joint instability: an in vivo cineradiographic investigation.

Although range of motion has been considered the best parameter to quantify atlantoaxial instability, no other kinematic parameters have been determined for dynamic quantification. The objectives of this study were to investigate the kinematics of the normal and pathologic atlantoaxial joints by cineradiography and to determine the in-vivo kinematic parameters, if any, for the quantification of atlantoaxial instability. Sagittal plane motion of the atlantoaxial joints was analyzed by cineradiography in 12 healthy volunteers and 15 patients with atlantoaxial subluxation. In both flexion and extension, C1-C2 sagittal rotation and C1 translation in the sagittal plane were measured continuously to determine the time-displacement curves for both parameters. All patients with atlantoaxial subluxation and seven of the volunteers had the sigmoid pattern in their time-displacement curves in sagittal rotation. In these cases, atlantoaxial motion showed different points of the onset of rapid increase in motion in their sigmoid curves between flexion and extension. The discrepancy between these points was more significant in the patients than in the volunteers. In most of the patients who had atlantoaxial instability, subluxation occurred when the atlantoaxial joints were still in a more extended position and they were reduced when they were still in more flexed position. The discrepancy showed characteristics similar to those of the neutral zone observed during in vitro investigations, suggesting that it becomes a good indicator of in vivo atlantoaxial instability.

Mid-term clinical results of Graf stabilization for lumbar degenerative pathologies. a minimum 2-year follow-up.

BACKGROUND CONTEXT: Spinal fusion has some adverse effects, such as nonunion and pain at the site of grafted bone, and fusion with rigid spinal instrumentation especially may have the possibility of increasing mechanical stress on the segments adjacent to the site of fusion. The theory of the Graf system is that it will decrease adjacent disc deterioration because of maintenance of regional lordosis with flexibility and restriction of the motion of unstable segments without rigid spinal fusion. PURPOSE: To assess the clinical and radiologic results of Graf stabilization for lumbar degenerative disorders with minimal or mild instability. STUDY DESIGN: This is a retrospective study examining the mid-term results of Graf stabilization. PATIENT SAMPLE: In total, 59 patients underwent Graf ligamentoplasty and adequate decompression from April 1993 to September 1997. The subjects were 30 men and 29 women, and the mean age at the time of surgery was 60.6 years, ranging from 23 to 82 years. The average follow-up period was 3 years and 5 months, ranging from 2 years to 5 years and 10 months. OUTCOME MEASURES: We evaluated the surgical results using a scoring system, a visual analog scale, and radiological measurements. METHODS: The results were assessed according to a clinical scoring system established by the Japanese Orthopaedic Association (JOA score) and ratings based on a visual analog scale. Through analysis of x-ray images, the sagittal alignment (regional lordosis) and the range of motion (ROM) of the stabilized segments were measured in all cases, and the percentage of segments slipping and posterior disc height were determined for 29 patients with degenerative spondylolisthesis. RESULTS: Clinical scores and low back pain ratings based on a visual analog scale were significantly improved at the time of final follow-up compared with the preoperative values. Regional alignment of the operative segments was maintained in lordosis at the time of final follow-up. Preoperative ROM was significantly reduced at the time of final follow-up. There were no statistical differences in percentage of slippage or percentage of posterior disc height between the final follow-up values and the preoperative values. CONCLUSIONS: Our clinical results indicate that the Graf system is a suitable treatment option for mild and early lumbar degenerative diseases with minimum flexion instability of less than 10 degrees.

Preventive and therapeutic vaccines for human papillomavirus-associated cervical cancers.

'High risk' genotypes of the human papillomavirus (HPV), particularly HPV type 16, are the primary etiologic agent of cervical cancer. Thus, HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. Sexual transmission of HPV may be prevented by the generation of neutralizing antibodies that are specific for the virus capsid. In ongoing clinical trials, HPV virus-like particles (VLPs) show great promise as prophylactic HPV vaccines. Since the capsid proteins are not expressed at detectable levels by basal keratinocytes, therapeutic vaccines generally target other nonstructural viral antigens. Two HPV oncogenic proteins, E6 and E7, are important in the induction and maintenance of cellular transformation and are coexpressed in the majority of HPV-containing carcinomas. Therefore, therapeutic vaccines targeting these proteins may provide an opportunity to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 are administered in live vectors, in peptides or protein, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should they fulfill their promise, these vaccines may prevent HPV infection or control its potentially life-threatening consequences in humans.

In vitro biomechanical investigation of the stability and stress-shielding effect of lumbar interbody fusion devices.

OBJECT: Interbody fusion devices are rapidly gaining acceptance as a method of ensuring lumbar interbody arthrodesis. Although different types of devices have been developed, the comparative reconstruction stability remains controversial. It also remains unclear how different stress-shielded environments are created within the devices. Using a calf spine model, this study was designed to compare the construct stiffness afforded by 11 differently designed lumbar interbody fusion devices and to quantify their stress-shielding effects by measuring pressure within the devices. METHODS: Sixty-six lumbar specimens obtained from calves were subjected to anterior interbody reconstruction at L4-5 by using one of the following interbody fusion devices: four different threaded fusion cages (BAK device, BAK Proximity, Ray TFC, and Danek TIBFD), five different nonthreaded fusion devices (oval and circular Harms cages, Brantigan PLIF and ALIF cages, and InFix device); two different types of allograft (femoral ring and bone dowel) were used. Construct stiffness was evaluated in axial compression, torsion, flexion, and lateral bending. Prior to testing, a silicon elastomer was injected into the cages and intracage pressures were measured using pressure needle transducers. CONCLUSIONS: No statistical differences were observed in construct stiffness among the threaded cages and nonthreaded devices in most of the testing modalities. Threaded fusion cages demonstrated significantly lower intracage pressures compared with nonthreaded cages and structural allografts. Compared with nonthreaded cages and structural allografts, threaded fusion cages afforded equivalent reconstruction stiffness but provided more stress-shielded environment within the devices.

Regression of gastric mucosa-associated lymphoid tissue lymphoma with reduced telomerase activity after eradication of Helicobacter pylori.

Recently, telomerase activity has been demonstrated in a large number of malignant tumors whereas its activity is not detected in most normal somatic cells suggesting its role in the immortalization process. Here we report the first investigation of telomerase activity in a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Elevated telomerase activity was detected in biopsy specimens of the lymphoma. After eradication of Helicobacter pylori, the level of telomerase activity returned to normal with histological regression of the lymphoma. The telomerase activity was associated with the disease activity of the gastric MALT lymphoma after eradication therapy in the present case.

Multiseptate gallbladder with cholelithiasis diagnosed incidentially in an elderly patient.

A 70-year-old woman with rheumatoid arthritis was admitted to our hospital because of gastric ulcers. Abdominal echography incidentally revealed that the patient's gallbladder was multiseptate, an extremely rare anomaly. The diagnosis was confirmed by endoscopic retrograde cholangiography. This is the 26th case of multiseptate gallbladder in the world literature, but the patient is the oldest yet recorded with this condition. Furthermore, unlike most patients with multiseptate gallbladder, she had no biliary symptoms with concomitant cholelithiasis.

Augmentation of an anterior solid rod construct with threaded cortical bone dowels. A biomechanical study.

STUDY DESIGN: This static, nondestructive, in vitro biomechanical study examines anterior solid rod construct stiffness following the addition of multilevel, threaded cortical bone dowels in a bovine model. A comparison is made with a clinically relevant posterior construct with and without an anterior release. OBJECTIVES: To determine if the addition of solid, multilevel disc space implants will increase construct rigidity, while maintaining or enhancing anterior column length. SUMMARY OF BACKGROUND DATA: Anterior instrumentation for thoracolumbar and lumbar scoliosis has achieved greater correction and preserved distal motion segments; however, kyphosis over the instrumented segments and nonunion have been observed more frequently than with posterior segmental spinal instrumentation. METHOD: Fifteen calf spines underwent mechanical testing. Group A (n = 7) included anterior constructs: 1) intact, 2) anterior release/rod/rib graft (L2-L5), and 3) anterior release/rod/dowels (L2-L5). Group B (n = 8) included posterior constructs: 1) intact, 2) posterior rod without anterior release (T13-L5), 3) posterior rod (T13-L5)/anterior release/rib graft (L2-L5). The protocol included axial compression (-600 N), axial rotation (+7 Nm), flexion/extension (+7.5 Nm), and lateral bending (+7.5 Nm). An anterior extensometer measured segmental displacements to calculate construct stiffness. Lateral radiographs evaluated alignment for the anterior constructs. Statistical analysis involved a one way analysis of variance (ANOVA) and a Student-Newman-Keuls post hoc test. RESULTS: All reconstructions restored stiffness to intact values with the exception of the dowels alone in axial rotation. The rod/dowel construct was stiffer than all other groups in axial compression, flexion/extension, and lateral bending, with the exception of the posterior rod without discectomy, which was superior in flexion and statistically similar in extension, lateral bending, and axial rotation. The anterior construct with rib graft was equivalent to the posterior construct with rib graft in all modes of testing. The dowels created greater lordosis than the bicortical rib grafts. CONCLUSIONS: Disc space augmentation increased stiffness except in axial rotation, in which values were restored to the intact level. Stiffness was superior to a clinically relevant posterior instrumentation comparison group following anterior release, and was equivalent to a posterior construct without anterior release except in anterior flexion. In addition, the implants enhanced lordosis. Increased rigidity should improve rates of arthrodesis, while maintenance of sagittal alignment may prevent pathologic compensatory curves in adjacent spinal segments. Further research is required to determine the optimal method of achieving structural interspace support.

Role of the sulphate assimilation pathway in utilization of glutathione as a sulphur source by Saccharomyces cerevisiae.

Mutants unable to grow on medium containing glutathione as a sole source of sulphur (GSH medium) were isolated from Saccharomyces cerevisiae strains carrying met17(deficiency of O-acetylserine and O-acetylhomoserine sulphydrylase). They were defective in the high-affinity glutathione transport system, GSH-P1. Newly acquired mutations belonged to the same complementation group, gsh11. However, it became apparent that gsh11 conferred the mutant phenotype not by itself but in collaboration with met17. Moreover, mutations conferring the defect in sulphate assimilation made the cell unable to grow on GSH medium in collaboration with gsh11. From this finding, we propose that the sulphate assimilation pathway acts as a sulphur-recycling system and that this function is especially vital to the cell when the supply of glutathione is limited.

Static and fatigue biomechanical properties of anterior thoracolumbar instrumentation systems. A synthetic testing model.

STUDY DESIGN: A mechanical testing standard for anterior thoracolumbar instrumentation systems was introduced, using a synthetic model. Twelve recent instrumentation systems were tested in static and fatigue modes. OBJECTIVES: To establish the testing standard for anterior thoracolumbar instrumentation systems using a synthetic model and to evaluate the static and fatigue biomechanical properties of 12 anterior thoracolumbar instrumentation systems. SUMMARY OF BACKGROUND DATA: Although numerous studies have been performed to evaluate the biomechanics of anterior spinal instrumentation using a cadaveric or animal tissue, problems of specimen variation, lack of reproducibility, and inability to perform fatigue testing have been pointed out. In no studies has a precise synthetic testing standard for anterior thoracolumbar instrumentation systems been described. METHODS: An ultra-high-molecular-weight polyethylene cylinder was designed according to the anatomic dimensions of the vertebral body. Two cylinders spanned by spinal instrumentation simulated a total corpectomy defect, and a compressive lateral bending load was applied. The instrumentation assembly was precisely standardized. The static destructive and fatigue tests up to 2 million cycles at three load levels were conducted, followed by the failure mode analysis. Twelve anterior instrumentation systems, consisting of five plate and seven rod systems were compared in stiffness, bending strength, and cycles to failure. RESULTS: Static and fatigue test parameters both demonstrated highly significant differences between devices. The stiffness ranged from 280.5 kN/m in the Synthes plate (Synthes, Paoli, PA) to 67.9 kN/m in the Z-plate ATL (SofamorDanek, Memphis, TN). The Synthes plate and Kaneda SR titanium (AcroMed, Cleveland, OH) formed the highest subset in bending strength of 1516.1 N and 1209.9 N, respectively, whereas the Z-plate showed the lowest value of 407.3 N. There were no substantial differences between plate and rod devices. In fatigue, only three systems: Synthes plate, Kaneda SR titanium, and Olerud plate (Nord Opedic AB, Sweden) withstood 2 million cycles at 600 N. The failure mode analysis demonstrated plate or bolt fractures in plate systems and rod fractures in rod systems. CONCLUSIONS: The biomechanical testing standard for anterior thoracolumbar instrumentation systems was successfully designed. It provided a repeatable and consistent experimental condition and controlling dimensional and surgical factors. The comparison of 12 instrumentation systems highlights the importance of mechanically balanced device design without a weak link in the development of instrumentation.

Does spinal instrumentation influence the healing process of posterolateral spinal fusion? An in vivo animal model.

STUDY DESIGN: An in vivo sheep model was used to investigate the effect of spinal instrumentation on the healing process of posterolateral spinal fusion. OBJECTIVES: To examine the role of spinal instrumentation during the healing process of posterolateral fusion. SUMMARY OF BACKGROUND DATA: In long bone fractures, internal fixation improves the union rate but does not accelerate the healing process. Spinal instrumentation also improves the fusion rate in spinal arthrodesis. However, it remains unclear whether the use of spinal instrumentation expedites the healing process of spinal fusion. METHODS: Sixteen sheep underwent posterolateral spinal arthrodeses at L2-L3 and L4-L5 using equal amounts of autologous bone. One of those segments was selected randomly to be augmented with transpedicular screw fixation (Texas Scottish Rite Hospital spinal system). The animals were killed at 8 weeks or 16 weeks after surgery. Fusion status was evaluated by biomechanical testing, manual palpation, plain radiography, computed tomography, and histology. RESULTS: Instrumented fusion segments demonstrated significantly higher stiffness than did uninstrumented fusions at 8 weeks after surgery. Radiographic assessment and manual palpation showed that the use of spinal instrumentation improved the fusion rate at 8 weeks (47% versus 38% in radiographs, 86% versus 57% in manual palpation). Histologically, the instrumented fusions consisted of more woven bone than the uninstrumented fusions at 8 weeks after surgery. The 16-week-old fusion mass was diagnosed biomechanically, radiographically, and histologically as solid, regardless of pedicle screw augmentation. CONCLUSION: The current study's results demonstrated that spinal instrumentation creates a stable mechanical environment to enhance the early bone healing of spinal fusion.

Osteogenic protein versus autologous interbody arthrodesis in the sheep thoracic spine. A comparative endoscopic study using the Bagby and Kuslich interbody fusion device.

STUDY DESIGN: Using an in vivo interbody arthrodesis model, the efficacy of the Bagby and Kuslich (BAK) device packed with recombinant human osteogenic protein-1 (rhOP-1) was evaluated. OBJECTIVES: To compare the efficacy of osteogenic protein with that of autograft for interbody arthrodesis, with fusion success based on biomechanical, histologic, and radiographic analyses. SUMMARY OF BACKGROUND DATA: The use of recombinant human bone morphogenetic proteins (rhBMPs) as osteoinductive bone graft substitutes or expanders has recently gained considerable research interest, particularly when applied in posterolateral arthrodesis. However, whether these results can be extrapolated to a successful interbody spinal arthrodesis remains uncertain. METHODS: Twelve sheep underwent a multilevel thoracic spinal decompression by thoracoscopic approach. Three noncontiguous destabilization sites (T5-T6, T7-T8, T9-T10) were prepared and randomly treated as follows. Control group treatments were nonsurgical, destabilization alone, and empty BAK. Experimental groups were treated with autograft alone, BAK device packed with autograft, or BAK device packed with rhOP-1. Four months after surgery, interbody fusion status was quantified by biomechanical testing, computed tomography, microradiography, and histomorphometry. RESULTS: Results of biomechanical analysis showed statistically higher segmental stiffness levels when comparing the control and experimental groups with four of the five testing methods (P < 0.05). Computed tomography and microradiography characterized destabilization alone as producing one fusion in six preparations; the empty BAK, two in six;, autograft alone, four in eight; BAK with autograft, five in eight; and BAK with rhOP-1 group, six in eight-all evidenced by woven trabecular bone spanning the fusion sites. Histomorphometry yielded significantly more trabecular bone formation at the fusion sites in the three experimental groups than in the two control groups (P < 0.05). CONCLUSIONS: Interbody spinal fusions showing biomechanical and histomorphometric equivalency to autologous fusions have been achieved with rhOP-1. The functional unit stability and histologic osteointegration evidenced by the BAK/rhOP-1 complex shows this interbody arthrodesis technique to be a viable alternative toconventional autologous iliac crest, thereby obviating the need for an iliac crest donor site and associated patient morbidity.

Biomechanical analysis of anterior versus circumferential spinal reconstruction for various anatomic stages of tumor lesions.

STUDY DESIGN: Spinal reconstruction procedures for metastasis evaluated biomechanically using human cadaver specimens. OBJECTIVE: To investigate the stiffness of anterior versus circumferential spinal reconstructions for different anatomic stages of tumor lesions. SUMMARY OF BACKGROUND DATA: Metastatic tumors predominantly involve the vertebral bodies. Although anterior instrumentation and strut grafts provide excellent stability, it remains unclear to what extent vertebral destruction requires anterior reconstructions alone versus combined anterior and posterior procedures. METHODS: Ten human cadaveric thoracolumbar spines were used. The L1 vertebral body and posterior elements were resected sequentially based on Weinstein's anatomic zone classification for tumor lesions. Anterior reconstruction was performed between T12 and L2 using an iliac strut graft and the Kaneda SR system (AcroMed, Cleveland, OH). For circumferential reconstruction, the Cotrel-Dubousset hook and rod system was combined with the anterior reconstruction procedure. Experimental groups included the intact condition and five reconstruction stages: anterior reconstructions for corpectomy, subtotal and total spondylectomies, and circumferential reconstructions for subtotal and total spondylectomies. Nondestructive biomechanical testing was performed under four different loading modes. RESULTS: All the reconstruction groups except anterior instrumentation alone for total spondylectomy returned stiffness to a level equivalent or higher to that of the intact spine. There were no statistical differences observed between anterior and circumferential reconstruction for subtotal spondylectomy. Anterior instrumentation alone for total spondylectomy did not restore stiffness to the intact level, and demonstrated significantly lower stiffness than that of circumferential reconstruction. CONCLUSIONS: For corpectomy or subtotal spondylectomy, anterior reconstruction alone can provide stiffness equivalent to circumferential reconstruction. However, total spondylectomy significantly reduces the anterior reconstruction stiffness, suggesting the need for combined anterior and posterior procedures.

Dynamic motion analysis of normal and unstable cervical spines using cineradiography. An in vivo study.

STUDY DESIGN: Cervical motion patterns were analyzed in a normal population and in patients with cervical instability by using cineradiography. OBJECTIVES: To determine normal and pathologic motion patterns in the cervical spine through an in vivo continuous motion analysis. SUMMARY OF BACKGROUND DATA: Cineradiographic techniques have been used in a limited number of studies to quantify spinal motion. There is a paucity of information regarding dynamic motion patterns in normal and pathologic cervical spines. METHODS: Ten healthy subjects and 12 patients with unstable cervical spines (C1-C2 subluxation caused by rheumatoid arthritis, n = 10; instability below C2, n = 2) were studied. Cervical motion during flexion from the maximum extension position was recorded using cineradiography. Cervical segmental motions (C1-C2 to C5-C6) were continuously measured through quantifying cineradiographic images projected on a digitizer. RESULTS: Normal cervical spines showed a well-regulated stepwise motion pattern that initiated at C1-C2 and transmitted to the lower segments with time lags. Pathologic spines showed a different order of onset of segmental motion. In patients with rheumatoid arthritis who had atlantoaxial subluxation, C1-C2 motion initiated significantly earlier than C2-C3 motion. In patients with segmental instability below C2, motion in the unstable segments preceded that in the upper intact segments. CONCLUSIONS: Different motion patterns were observed between normal and pathologic cervical spines. Cineradiographic motion analysis is a valuable adjunctive technique, especially in diagnosis or evaluation of conditions that cannot be identified through conventional radiographic examination.

Serial electroencephalographic findings in patients with MELAS.

To clarify the electroencephalographic characteristics of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), the medical records and electroencephalograms of six patients with MELAS and two of their relatives with MELA (mitochondrial myopathy, encephalopathy, and lactic acidosis, without strokelike episodes) were retrospectively reviewed. All have a point mutation in the mitochondrial DNA at nucleotide position 3243. The electroencephalograms (n = 79) were divided into four groups according to the time relation to the strokelike episode: (1) before the first strokelike episode, (2) within 5 days after the strokelike episode (acute stage), (3) between 6 days and 1 month after the strokelike episode (subacute stage), and (4) more than 1 month after the strokelike episode (chronic stage). In the acute stage, 10 of the 11 electroencephalograms (9 strokelike episodes in four patients) revealed focal high-voltage delta waves with polyspikes (FHDPS), which were recognized as ictal electroencephalogram. Ictal events during FHDPS included focal clonic or myoclonic seizure and migrainous headache. In the subacute and chronic stages, focal spikes or sharp waves and 14- and 6-Hz positive bursts were frequently recorded. The authors' results suggest that FHDPSs present a reliable and accurate indicator of a strokelike episode in patients with MELAS.