Synthetic bone: Design by additive manufacturing.

A broad range of synthetic trabecular-like metallic lattices are 3D printed, to study the extra design freedom conferred by this new manufacturing process. The aim is to propose new conceptual types of implant structures for superior bio-mechanical matching and osseo-integration: synthetic bone. The target designs are 3D printed in Ti-6Al-4V alloy using a laser-bed process. Systematic evaluation is then carried out: (i) their accuracy is characterised at high spatial resolution using computed X-ray tomography, to assess manufacturing robustness with respect to the original geometrical design intent and (ii) the mechanical properties - stiffness and strength - are experimentally measured, evaluated, and compared. Finally, this new knowledge is synthesised in a conceptual framework to allow the construction of so-called implant design maps, to define the processing conditions of bone tailored substitutes, with focus on spine fusion devices. The design criteria emphasise the bone stiffness-matching, preferred range of pore structure for bone in-growth, manufacturability of the device and choice of inherent materials properties which are needed for durable implants. Examples of the use of such maps are given with focus on spine fusion devices, emphasising the stiffness-matching, osseo-integration properties and choice of inherent materials properties which are needed for durable implants. STATEMENT OF SIGNIFICANCE: We present a conceptual bio-engineering design methodology for new biomedical lattices produced by additive manufacturing, which addresses some of the critical points in currently existing porous implant materials. Amongst others: (i) feasibility and accuracy of manufacturing, (ii) design to the elastic properties of bone, and (iii) sensible pores sizes for osseointegration. This has inspired new and novel geometrical latticed designs which aim at improving the properties of intervertebral fusion devices. In their fundamental form, these structures are here fabricated and tested. When integrated into medical devices, these concepts could offer superior medical outcomes.

Nanocavities and germanium nanocrystals produced by Ge ion implantation in fused silica.

High-resolution SEM images of germanium nanocrystals (Ge-nc) synthesized by ion implantation in fused silica samples annealed at temperatures below and above the melting point of Ge show a strong size-selective depth-distribution of nanostructures, as evidenced by the correlation between the dimension of the observed objects and the local concentration of implanted Ge measured by Rutherford backscattering spectroscopy (RBS). Whereas the Ge-nc nucleation seems to obey the Ostwald ripening process in samples annealed below 900 °C, Ge desorption effects, non-uniform in depth, in conjunction with the formation of large and spherical nanocavities, become dominant for annealing performed above the solid-liquid phase transition of Ge. Measurements for different annealing times at 1050 °C show two distinct processes in the Ge desorption dynamics: the first is related to direct Ge outgassing effects during the nucleation of Ge-nc, which occurs within the first minutes of the thermal annealing, while the second is due to the release of Ge from Ge-nc, associated with the formation of nanocavities. The formation rate of these nanocavities is more efficient at greater depth than in the vicinity of the sample surface. It appears to be strongly dependent on the local concentration of defects, responsible for the reduction of the Ge diffusion, and to be related to the breaking of Ge-O and Si-Ge bonds at the Ge-nc/SiO(2) interface.

Changes in fiber tract integrity and visual fields after anterior temporal lobectomy.

OBJECTIVE: To investigate postoperative changes in fiber tract integrity in patients with temporal lobe epilepsy (TLE) following anterior temporal lobectomy (ATL) and to determine whether postoperative changes are 1) stable vs progressive and 2) related to visual field defects. METHODS: Diffusion tensor imaging (DTI) was obtained in 7 patients with TLE before, 2 months after, and 1 year after ATL. Changes in fractional anisotropy (FA) were evaluated in a whole-brain voxel-wise analysis, as well within specific fiber tracts. Repeated-measures analysis of variance was performed to examine the time course of FA changes within ipsilateral and contralateral fiber tracts. Quantitative visual field analysis was performed to determine whether decreases in regional FA were related to the extent or location of visual field defects. RESULTS: Patients showed decreased FA 2 months post-ATL in ipsilateral fiber tracts transected during surgery (parahippocampal cingulum, uncinate fasciculus, inferior longitudinal fasciculus, and fornix), as well as in fiber tracts not directly transected (inferior fronto-occipital fasciculus and corpus callosum). Additional decreases in FA were not observed from 2 months to 1 year post-ATL. Visual field defects in most patients were characterized by incomplete quadrantanopsias. However, FA reductions in one patient extended into temporo-occipital cortex and the splenium of the corpus callosum and were associated with a complete hemianopia. CONCLUSIONS: Wallerian degeneration is apparent 2 months following unilateral ATLs in ipsilateral fibers directly and indirectly affected during surgery. These changes do not appear to progress over the course of a year, but may correlate with the nature and extent of postoperative visual field defects.

Deep brain stimulation of the subthalamic nucleus facilitates coordination of hand preshaping in Parkinson's disease.

Several studies have found that Parkinson's disease (PD) disrupts the organization of complex motor sequences regardless of the influence of parkinsonian medications. A clear candidate for the neural bases of such deficits, which we term "coordinative," is the failure to integrate propioceptive and visual information by cortico-striatal circuits in a timed fashion. Recent reports, however, have indicated that deep-brain stimulation of the subthalamic nucleus (STN DBS) may result in an improvement in coordinative deficits beyond the amelioration of "intensive deficits" such as bradykinesia and scaling errors. The present study examined the spatio-temporal organization underlying the shaping of the hand during reaching to grasp objects differing in shape. Six PD patients ON and OFF their STN DBS when OFF their concomitant medications and six age-matched controls participated in this study. STN DBS improved the coordination involved in preshaping the hand while grasping. We discuss these results in light of our earlier work with PD patients on and off dopamine replacement therapy.

Evidence of localized amorphous silicon clustering from Raman depth-probing of silicon nanocrystals in fused silica.

Silicon nanocrystals (Si-nc) and amorphous silicon (α-Si) produced by silicon implantation in fused silica have been studied by micro-Raman spectroscopy. Information regarding the Raman signature of the α-Si phonon excitation was extracted from Raman depth-probing measurements using the phenomenological phonon confinement model. The spectral deconvolution of the Raman measurements recorded at different laser focusing depths takes into account both the Si-nc size variation and the Si-nc spatial distribution within the sample. The phonon peak associated with α-Si around 470 cm(-1) is greatest for in-sample laser focusing, indicating that the formation of amorphous silicon is more important in the region containing a high concentration of silicon excess, where large Si-nc are located. As also observed for Si-nc systems prepared by SiO(x) layer deposition, this result demonstrates the presence of α-Si in high excess Si implanted Si-nc systems.

Electroluminescence microspectroscopy of silicon nanocrystals obtained by Si(+) ion implantation in SiO(2).

Room-temperature electroluminescence (EL) has been measured at both macroscopic and microscopic levels from metal-oxide-semiconductor devices containing silicon nanocrystals (Si-nc) embedded in silicon dioxide (SiO(2)) obtained by high-temperature annealing (1050 and 1100 °C) after Si(+) ion implantation. It is found that spatially integrated (macroscopic) EL is dominated by a near-infrared band centered where the photoluminescence (PL) band of Si-nc (from 700 to 1000 nm) is located. However, on a microscopic scale, EL emission is inhomogeneous, the sample surface exhibiting many visible spots of micron-order diameter. EL spectra from a microscopic surface of ∼1 µm(2)(µEL) on visible spots have revealed dominant contributions between ∼550 and ∼650 nm, attributed to oxide defects. These spectral features rapidly decrease with distance from a bright spot, while lower-intensity near-infrared contributions (750-950 nm) remain unaffected up to relatively large distances before eventually becoming extinct. The macroscopic EL measurements can be explained as a superposition of the µEL and PL spectra. A luminescent mechanism is proposed in which charge carriers mostly tunnel through high-defect-density channels in the oxide, yielding bright visible spots, while Si-nc in these channels and their surroundings contribute to the luminescence by hosting electron-hole recombinations (EL) and/or exhibiting PL due to optical excitation from the nearby visible EL spot.

Perceptual decision making for baseball pitch recognition: using P300 latency and amplitude to index attentional processing.

This study was designed to examine the perceptual and attentional processes associated with the effects of administering a cost-benefit precuing paradigm to intermediate and advance-level baseball batters. Psychophysiological and performance data obtained from 10 advanced and 10 intermediate-level players were compared. A total of 400 pitches (200 fastballs, 200 curveballs) was randomly presented via a large projection screen, and participants pressed one of two buttons to indicate the type of pitch thrown. Verbal precues were given for 300 of the pitches. Of those, 75% were valid, and 25% were invalid. Electroencephalographic data collected from the P location was used to assess the latency and amplitude of P300. Analysis of variance (Skill Level x Precue x Pitch) for P300 and reaction time (RT) indicated that intermediate batters produced shorter P300 latencies, larger P300 amplitudes, longer RTs, and less correct responses than the advanced batters; the effects were more pronounced for the curveballs. These results suggest that intermediate batters are less efficient in their perceptual decision-making processes due to greater limitations in attentional capacity when compared with advanced batters.

Case of the month: March 1999--A 26 year old HIV positive male with dura based masses.

A 26-year-old male with AIDS presented with a chief complaint of headaches and neck pain. An MRI revealed two enhancing extra-axial dura based masses, one in the area of the left sphenoid wing and one at the level of C2-3. In both cases, microscopic sections showed actin positive spindle cell neoplasms with long slender nuclei, consistent with leiomyomas. Both tumors were positive for Epstein Barr virus by in situ hybridization. This case report serves to emphasize the importance of considering soft tissue tumors such as leiomyoma in the differential diagnosis of mass lesions that occur in the central nervous system in AIDS and discusses the role of EBV in tumorigenesis.

Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases.

The authors studied complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases (LM). One hundred twenty consecutive patients with LM (71 females and 49 males) ranging in age from 10 to 72 years (median 42 years) were treated with involved-field radiotherapy and intraventricular chemotherapy using an Ommaya reservoir and intraventricular catheter system. The diagnosis of LM was determined by a combination of clinical presentation (114 patients); cerebrospinal fluid cytological studies (100); or neuroradiographic studies (42). Systemic tumor histological findings included breast (34 patients); non-Hodgkin's lymphoma (22); melanoma (16); primitive neuroectodermal tumors including medulloblastoma (10); glial neoplasms, leukemia, small cell lung, nonsmall cell lung, and colon (six each); prostate and kidney (three each); and gastric cancers (two). Sixteen patients, all with non-Hodgkin's lymphoma, also had acquired immune deficiency syndrome. Patients received one to four (median two) chemotherapeutic drugs and underwent a total of 1110 cycles of intraventricular chemotherapy (median 10). Intraventricular chemotherapy administration and diagnostic Ommaya reservoir punctures totaled 4400, with a median of 46 per patient. Complications included aseptic/chemical meningitis (52 patients); myelosuppression due to intraventricular chemotherapy (21); catheter-related infections (nine); unidirectional catheter obstruction (six); intraventricular catheter malpositioning (two); Ommaya reservoir exposure (two); leukoencephalopathy (two); and chemotherapy-related myelopathy (one). There were no treatment-related deaths; however, seven patients (6%) required additional surgery for either catheter repositioning (two) or reservoir removal (five). Seven patients with catheter-related infections were treated successfully with intraventricular and systemic antibiotic drugs, thereby preserving the Ommaya system. The authors conclude that Ommaya reservoirs are convenient and pharmacologically rational systems for administering intraventricular chemotherapy. Overall, serious complications requiring surgery are infrequent (6%) and most often secondary to catheter infections, Ommaya reservoir exposure, or initial catheter malpositioning. In the majority of instances, catheter infections may be managed medically, as may the most common complications of intraventricular chemotherapy including aseptic meningitis (43% of patients) and myelosuppression (18%).

Concurrent carboplatin and iodine-125 brachytherapy for recurrent glioblastoma multiforme.

Toxicity and safety study of concurrent carboplatin chemotherapy and iodine-125 (I-125) brachytherapy. I-125 brachy therapy has an established albeit limited role in surgically accessible recurrent gliomas. Carboplatin has anti-tumoral; activity against gliomas and demonstrated sensitization of tumor to radiotherapy. In 15 patients (age range 30-77 years; median 53) with recurrent glioblastoma multiforme, stereotactically placed catheters were afterloaded with I-125 sources. A median 50 Gy minimum treatment volume dose was delivered during a 100 h period in conjunction with continuous infusion carboplatin (100 mg/m(2)/20 h x 5). Tumor volumes ranged from 13 to 63 cm(3) (median, 32 cm(3)). Early complications included: headache (n=7), transient exacerbations of pre existing neurologic deficits (n=5), seizures (n=2), nausea/vomiting (n=2), myelosuppression (n=2) and a catheter site wound CSF leak (n=1). Late complications included: steroid dependency (n=10), carcinomatous meningitis in association with hydrocephalus (n=1) and radiation-induced necrosis requiring reoperation (n=6). All patients were evaluable with a median survival of 10 months. In 12 patients, best clinical and neuroradiographic response was stable disease all of whom died of recurrent tumor (local recurrence in 11; CSF dissemination in 1). In 3 patients best response was either complete (n=2) or partial (n=1) all of whom are alive with a median follow-up of 31 months. I-125 brachytherapy with concurrent carboplatin chemotherapy is associated with an acceptable level of toxicity, has anti-tumoral activity and warrants further investigation in carefully selected patients with recurrent gliomas.

Maximizing performance feedback effectiveness through videotape replay and a self-controlled learning environment.

This study was designed to examine whether participants who could control the schedule of performance feedback (KP) would learn differentially from those who received a rigid feedback schedule while learning a complex task. Participants (N = 48) were randomly assigned to self-controlled KP (SELF), summary KP (SUMMARY), yoked control (YOKE), or knowledge of results only (KR) conditions. Data collection consisted of an acquisition phase and a 4-day retention phase during which right-handed participants performed a left-handed ball throw. Overall, throwing form improved across trial blocks during acquisition, with the SUMMARY, SELF, and YOKE groups showing more improvement than the KR group. During retention, the SELF group retained a higher level of throwing form and accuracy in comparison to the other groups. Results suggest that when given the opportunity to control the feedback environment, learners require relatively less feedback to acquire skills and retain those skills at a level equivalent to or surpassing those who are given more feedback but receive it passively.

Stereotactic radiosurgery for metastatic brain tumors.

We report on a prospective phase TI study utilizing stereotactic radiosurgery for patients with intracranial parenchymal metastases. Fifty patients ranging in age from 38 to 77 years with 1 to 3 intraparenchymal brain metastases were treated with stereotactic radiosurgery either immediately following whole brain radiotherapy or at the time of intracranial disease progression following failure of whole brain radiotherapy. Twenty patients treated with adjuvant therapy received a median radiosurgical dose of 20 Gy. Thirty patients treated with salvage therapy received a median radiosurgical dose of 20 Gy. No immediate neurotoxicity was seen following radiosurgery however, 4 patients (8%) developed symptomatic radiation necrosis. Median survival was 6.5 and 6.0 months for patients treated with adjuvant and salvage radiosurgery respectively. In patients with oligometastatic brain metastases manifesting intracranial disease progression after whole brain radiotherapy, salvage radiotherapy appears to offer improved palliation when compared to retreatment with whole brain radiotherapy. The results of patients treated with up-front adjuvant radiosurgery when compared to historical controls treated with whole brain radiotherapy only are less clear as to benefit and require a phase III study before definitive recommendations can be made.

Early biopsy versus empiric treatment with delayed biopsy of non-responders in suspected HIV-associated cerebral toxoplasmosis: a decision analysis.

OBJECTIVE: To construct and evaluate a decision analytic model of proposed management strategies for HIV-infected patients presenting with cerebral mass lesions, radiographically compatible with toxoplasmosis, lymphoma, or other etiologies, assuming knowledge of Toxoplasma antibody status in serum. METHODS: Using decision analysis, we evaluated two management strategies, for patients found to be either Toxoplasma-seropositive or -negative, for whom an initial choice was made for early brain biopsy (EB) or for empiric therapy with delayed biopsy (ETDB) of non-responders. The outcome to be optimized was the percentage of patients alive at 12 months. Model variables included predictive value of toxoplasmosis serology, probabilities of treatment response and death within 14-21 days conditional on correct diagnosis, probability of operative death, probabilities of non-diagnostic brain biopsy conditional both on correct diagnosis and prior treatment. RESULTS: One and two-way sensitivity analyses, by Toxoplasma serostatus, led to the following conclusions (1) for Toxoplasma-seropositive patients, ETDB gives nearly equivalent outcomes to EB of all patients; (2) for Toxoplasma-seronegative patients, although both strategies have equivalent outcomes under baseline assumptions, EB is preferred if there are even small survival advantages for early versus delayed diagnosis of lymphoma or other conditions, or if risk of death within 14-21 days of ET exceeds 10% when correct diagnosis is not toxoplasmosis. CONCLUSION: Under plausible assumptions, Toxoplasma-seronegative patients will benefit from an early biopsy strategy.

Concurrent cisplatin therapy and iodine 125 brachytherapy for recurrent malignant brain tumors.

OBJECTIVE: Toxicity and safety study of concurrent cisplatin therapy and iodine 125 (125I) brachytherapy. BACKGROUND: Iodine 125 brachytherapy has an established role in surgically accessible recurrent tumors of brain. Cisplatin has antitumoral activity against glial neoplasms and has demonstrated sensitization of tumor to radiotherapy. DESIGN/METHODS: In 16 patients (age range, 13 to 68 years, median, 47 years), stereotactically placed catheters were afterloaded with 125I sources. A median 50-Gy minimum treatment volume dose was delivered during a 100-hour period along with cisplatin (20 mg/m2 per day for 5 days). Histologic diagnoses included glioblastoma multiforme (n = 11), anaplastic astrocytoma (n = 3), ependymoma (n = 1), and anaplastic oligodendroglioma (n = 1). Tumor volumes ranged from 7.0 to 73 cm3 (median, 25 cm3). RESULTS: Early complications included headache (n = 7), transient exacerbations of preexisting neurologic deficits (n = 5), seizures (n = 3), and nausea/vomiting (n = 3). Late complications included steroid dependency (n = 10), progressive dementia in the absence of recurrent tumor (n = 1), and radiation-induced necrosis (n = 9) requiring reoperation (n = 9). Fifteen of 16 patients were assessable, with a median follow-up time of 9.5 months. Brachytherapy was discontinued in one patient owing to an acute subdural hematoma. A partial response was seen in five patients, disease remained stable in seven patients, and disease progressed in three patients. CONCLUSIONS: We conclude that 125I brachytherapy with concurrent cisplatin therapy is associated with an acceptable level of toxic effects and warrants further investigation.

Multiple plasma cell granulomas of the central nervous system: case report.

Plasma cell granulomas of the central nervous system are exceedingly rare. Of the six well-documented cases that have been published to date, five plasma cell granulomas were intracranial and one was located in the spinal meninges. Multiple plasma cell granulomas of the central nervous system have not previously been reported. We now report a patient who had two plasma cell granulomas in the spinal meninges and one in the anterior cerebral falx. The histological findings that differentiate this rare lesion from other central nervous system lesions, such as plasmacytoma and meningioma, are discussed with a review of the literature.

Stereotactic radiosurgery for recurrent gliomas.

BACKGROUND: The treatment of recurrent gliomas is palliative; however, the local pattern of tumor recurrence permits retreatment with single fraction, high dose stereotactic radiotherapy or radiosurgery (RS). METHODS: Twenty patients (median Karnofsky performance status, 80), aged 8-62 years with recurrent gliomas, were treated with RS after failing adjuvant therapy. Tumor histologies included glioblastoma multiforme (5), anaplastic astrocytoma (10), fibrillary astrocytoma (4), and primitive neuroectodermal tumor (1). Tumor volumes ranged from 3-53.5 cc, with a median of 17 cc. RESULTS: Seven early and one late radiation complication were seen. All seven early radiation complications were due to raised intracranial pressure and resolved in all but one patient who died. Median follow-up in 19 evaluable patients was 8 months (range, 2-29 months). Fourteen patients died from progressive tumor (median survival, 7 months). Five patients, four with recurrent tumor, were alive (median follow-up, 19 months) with a median time-to-tumor progression of 9 months. CONCLUSIONS: Radiosurgery demonstrates modest efficacy with acceptable toxicity in selected patients with recurrent gliomas and warrants further investigation.

Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors.

Using the 9L experimental brain tumor model, we studied long-term tumor regression and immunologic consequences of tumor killing in a model of in vivo gene transfer of the herpes simplex virus 1 thymidine kinase (HSV-TK) gene and ganciclovir (GCV) treatments. Fibroblasts modified to produce retroviral vectors carrying the HSV-TK gene were implanted into established 9L brain tumors in Fischer 344 rats to carry out gene transfer. Animals were then treated with parenteral GCV. Significant tumor regression was seen following GCV treatments in short-term experiments (17 days) as quantified by measurements of tumor volume. In long-term studies, 7 of 32 (22%) treated animals survived 90 days. Histologic examination of the brains of the successfully treated animals demonstrated residual tumor cells and inflammatory cells consisting predominantly of macrophages/microglia and T cells in the hemisphere with the residual tumor cyst. Rats surviving 90 days rejected repeat tumor injections into the contralateral brain and flank, whereas identical tumor injections in naive animals resulted in both brain and flank tumors. The presence of significant anti-tumor immunity following HSV-TK and GCV treatments suggests that the immune system plays a critical role in the sustained tumor regressions associated with these treatments. These findings show that while HSV-TK and GCV treatments can result in long-term tumor regressions in this model, the success of these treatments could be improved by better understanding the role played by the host's immune systems.

Thymidine kinase-mediated killing of rat brain tumors.

Gene therapy has many potential applications in central nervous system (CNS) disorders, including the selective killing of tumor cells in the brain. A rat brain tumor model was used to test the herpes simplex virus (HSV)-thymidine kinase (TK) gene for its ability to selectively kill C6 and 9L tumor cells in the brain following systemic administration of the nucleoside analog ganciclovir. The HSV-TK gene was introduced in vitro into tumor cells (C6-TK and 9L-TK), then these modified tumor cells were evaluated for their sensitivity to cell killing by ganciclovir. In a dose-response assay, both C6-TK and 9L-TK cells were 100 times more sensitive to killing by ganciclovir (median lethal dose: C6-TK, 0.1 microgram ganciclovir/ml; C6, 5.0 micrograms ganciclovir/ml) than unmodified wild-type tumor cells or cultured fibroblasts. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to kill established brain tumors in rats as quantified by both stereological assessment of brain tumor volumes and studies of animal survival over 90 days. Rats with brain tumors established by intracerebral injection of wild-type or HSV-TK modified tumor cells or by a combination of wild-type and HSV-TK-modified cells were studied with and without ganciclovir treatments. Stereological methods determined that ganciclovir treatment eliminated tumors composed of HSV-TK-modified cells while control tumors grew as expected (p < 0.001). In survival studies, all 10 rats with 9L-TK tumors treated with ganciclovir survived 90 days while all untreated rats died within 25 days. Curiously, tumors composed of combinations of 9L and 9L-TK cells could be eliminated by ganciclovir treatments even when only one-half of the tumor cells carried the HSV-TK gene. While not completely understood, this additional tumor cell killing appears to be both tumor selective and local in nature. It is concluded that HSV-TK gene therapy with ganciclovir treatment does selectively kill tumor cells in the brain and has many potential applications in CNS disorders, including the treatment of cancer.