Fingers' vibration transmission and grip strength preservation performance of vibration reducing gloves.

The vibration isolation performances of vibration reducing (VR) gloves are invariably assessed in terms of power tools' handle vibration transmission to the palm of the hand using the method described in ISO 10819 (2013), while the nature of vibration transmitted to the fingers is ignored. Moreover, the VR gloves with relatively low stiffness viscoelastic materials affect the grip strength in an adverse manner. This study is aimed at performance assessments of 12 different VR gloves on the basis of handle vibration transmission to the palm and the fingers of the gloved hand, together with reduction in the grip strength. The gloves included 3 different air bladder, 3 gel, 3 hybrid, and 2 gel-foam gloves in addition to a leather glove. Two Velcro finger adapters, each instrumented with a three-axis accelerometer, were used to measure vibration responses of the index and middle fingers near the mid-phalanges. Vibration transmitted to the palm was measured using the standardized palm adapter. The vibration transmissibility responses of the VR gloves were measured in the laboratory using the instrumented cylindrical handle, also described in the standard, mounted on a vibration exciter. A total of 12 healthy male subjects participated in the study. The instrumented handle was also used to measure grip strength of the subjects with and without the VR gloves. The results of the study showed that the VR gloves, with only a few exceptions, attenuate handle vibration transmitted to the fingers only in the 10-200 Hz and amplify middle finger vibration at frequencies exceeding 200 Hz. Many of the gloves, however, provided considerable reduction in vibration transmitted to the palm, especially at higher frequencies. These suggest that the characteristics of vibration transmitted to fingers differ considerably from those at the palm. Four of the test gloves satisfied the screening criteria of the ISO 10819 (2013) based on the palm vibration alone, even though these caused amplification of handle vibration at the fingers. The fingers' vibration transmission performance of gloves were further evaluated using a proposed finger frequency-weighting Wf apart from the standardized Wh-weighting. It is shown that the Wh weighting generally overestimates the VR glove effectiveness in limiting the fingers vibration in the high (H: 200-1250 Hz) frequency range. Both the weightings, however, revealed comparable performance of gloves in the mid (M: 25-200 Hz) frequency range. The VR gloves, with the exception of the leather glove, showed considerable reductions in the grip strength (27-41%), while the grip strength reduction was not correlated with the glove material thickness. It is suggested that effectiveness of VR gloves should be assessed considering the vibration transmission to both the palm and fingers of the hand together with the hand grip strength reduction.

Differential protein acetylation induced by novel histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.

Screening for inhibitors of histone deacetylase by incorporating a spraying method to micro-arrayed compound screening.

We have developed a method of spraying assay reagents onto a target gel in the Micro-Arrayed Compound Screening ( micro ARCS) format. After application of target gels to compound sheets, subsequent reagents can be applied by spraying onto the target gel. The spraying method conserves on assay reagents by up to 10-fold, eliminates the need for casting additional agarose gels, and increases the throughput of a screen by 3-fold. To demonstrate the efficacy of applying the spraying method to micro ARCS, we screened over 600,000 compounds for inhibitors of histone deacetylase (HDAC). Commercially available HDAC substrate and reaction developer were sprayed directly onto the gel to initiate the reaction and to amplify the signal, respectively. Picks in the primary screen were retested at a density of 384 compounds per sheet in the micro ARCS format. IC(50) values for active compounds were confirmed in a 96-well plate assay. The screen identified several small molecule inhibitors of the enzyme, including members of several classes of known HDAC inhibitors. The combination of the high-density format of micro ARCS, the efficiency of the spraying method, and a timed sequence of adding assay reagents permitted a screening throughput of 200,000 tests an hour. We present the details of the screening format and the analysis of the hits from the screen.

Discovery of selective hydroxamic acid inhibitors of tumor necrosis factor-alpha converting enzyme.

Modification of the P(1)' substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-alpha converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-alpha in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P(1)' substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors.

Tandem interbody fusion grafting after cervical vertebrectomy.

STUDY DESIGN: A case is presented with clinical and radiologic follow-up assessment to evaluate the possible effectiveness of tandem interbody fusion grafting. OBJECTIVE: To design a technique for rescuing a long iliac crest bone autograft that is too short or must be shortened because of the undesirable shape some long iliac crest grafts can take. SUMMARY OF BACKGROUND DATA: Supplementing a larger piece of autograft with a smaller piece in tandem is suggested in this report as a potentially valuable technique for a surgeon presented with a large but inadequate piece of autograft. METHODS: Instead of requiring a second incision to remove iliac crest from the other side or an allograft, the technique described in this report uses a small piece of iliac crest laid in tandem with the original strut graft to span the vertebrectomy channel. RESULTS: A case of an anterior cervical vertebrectomy using a tandem strut graft resulted in good clinical and radiographic results. CONCLUSIONS: Tandem graft placement can salvage a graft that is of inadequate final length.

Biaryl ether retrohydroxamates as potent, long-lived, orally bioavailable MMP inhibitors.

A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).

Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770.

Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.

Results and risk factors for anterior cervicothoracic junction surgery.

OBJECT: Stabilization of the cervicothoracic junction (CTJ) requires special attention to the operative approach and biomechanical requirements of the fixation construct. In this study the authors assess the morbidity associated with the anterior approach to the CTJ and define risks that may lead to construct failure after anterior CTJ surgery. METHODS: Data obtained for 14 patients (six men and eight women, mean age 50.1 years) who underwent surgical stabilization of the CTJ via an anterior cervical approach were retrospectively reviewed to assess the anterior approach-related morbidity and the risks of construct failure. The mean follow-up period was 21.1 months. Four patients (29%) had previously undergone CTJ surgery; in 11 patients (64%) more than one motion segment was involved (two levels, six patients; three levels, four patients; four levels, one patient); allograft was placed in three (21%) of 14 graft sites; and anterior plates were used for reconstruction augmentation in eight patients (57%). Postoperatively all patients improved, although four patients had residual deficits or pain. Graft/plate failure, requiring surgical revision and/or halo placement, occurred in five patients (36%). One patient experienced transient recurrent laryngeal nerve palsy. Postoperatively, the authors classified patients into one of two groups: those in whom surgery was successful (nine cases) and those in whom it had failed (five cases). Analysis of the characteristics of these two groups revealed that male sex (p < 0.0365), multiple levels of involvement (p < 0.0378), and the use of allograft as compared with autograft (p < 0.0088) were significant risk factors for construct failure. Prior CTJ surgery (p < 0.053) tended to be associated with graft failure. CONCLUSIONS: Findings of this study, in the setting of these factors, indicate that anterior reconstruction alone may not meet the biomechanical needs of this spinal region and that supplementary fixation may be considered to augment stabilization for fusion success.

Characterization of matrix metalloproteinase inhibitors: enzymatic assays.

The matrix metalloproteinases (MMPs) are a family of tightly regulated proteases that are involved in the catabolic aspect of remodeling and maintenance of normal tissue, and more than 20 human MMPs have been identified thus far. The MMPs collectively degrade a broad range of protein components of the extracellular matrix. While some substrate overlap exists, individual MMPs have been shown to process certain substrates more efficiently than others. These differences raise the critical issue of whether broad-spectrum inhibitors, active against all MMPs, or selective inhibitors, targeted to a subset of enzymes, represent the optimal therapeutic strategy for a given disease. This suggests the need to assess the inhibition potency of test compounds across a range of MMP family members. Described in this unit is a method for the in vitro characterization of MMP inhibitors. The is used to determine the potency of test compounds as inhibitors of 8 representative MMPs through the measurement of their inhibition of cleavage of a fluorogenic substrate. Since this substrate is efficiently hydrolyzed by all MMPs in the screening assays presented here, the method is convenient for assessing the selectivity of inhibitors against multiple enzymes. A describes the activation of MMP zymogens.

Evaluation of the inhibition of other metalloproteinases by matrix metalloproteinase inhibitors.

Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.

Spinal cord arteriovenous fistulas involving the conus medullaris: presentation, management, and embryologic considerations.

BACKGROUND: Spinal cord arteriovenous fistulas (SCAVF) are uncommon congenital lesions that usually involve the most caudal aspects of the cord. We present three cases of SCAVF that illustrate the clinical manifestations and possible management options. The characteristic involvement of the conus medullaris and an associated tethered spinal cord in one of our patient suggests that a disorder of secondary neurulation may be involved in the formation of these arteriovenous shunt lesions. METHODS: Review of records and radiologic studies in three consecutive patients with SCAVF's treated at this institution. RESULTS: All three patients had SCAVF involving the lower lumbar spinal cord segments or the conus. One of the conus lesions was associated with tethering of the spinal cord. One small lesion (Type A) was treated surgically, whereas the two larger lesions (Type B) were treated using interventional neuroradiologic techniques. CONCLUSIONS: Both surgical and endovascular method have a role in management of these unusual spinal cord vascular malformations. The association with tethered cord suggests that the propensity for SCAVM to occur in the most caudal portions of the spinal cord may result from failure of secondary neurulation to properly develop the unique and complex vascular anatomy of the region.

Extrapore residues of the S5-S6 loop of domain 2 of the voltage-gated skeletal muscle sodium channel (rSkM1) contribute to the mu-conotoxin GIIIA binding site.

The tetradomain voltage-gated sodium channels from rat skeletal muscle (rSkM1) and from human heart (hH1) possess different sensitivities to the 22-amino-acid peptide toxin, mu-conotoxin GIIIA (mu-CTX). rSkM1 is sensitive (IC50 = 51.4 nM) whereas hH1 is relatively resistant (IC50 = 5700 nM) to the action of the toxin, a difference in sensitivity of >100-fold. The affinity of the mu-CTX for a chimera formed from domain 1 (D1), D2, and D3 from rSkM1and D4 from hH1 (SSSH; S indicates origin of domain is skeletal muscle and H indicates origin of domain is heart) was paradoxically increased approximately fourfold relative to that of rSkM1. The source of D3 is unimportant regarding the difference in the relative affinity of rSkM1 and hH1 for mu-CTX. Binding of mu-CTX to HSSS was substantially decreased (IC50 = 1145 nM). Another chimera with a major portion of D2 deriving form hH1 showed no detectable binding of mu-CTX (IC50 > 10 microM). These data indicate that D1 and, especially, D2 play crucial roles in forming the mu-CTX receptor. Charge-neutralizing mutations in D1 and D2 (Asp384, Asp762, and Glu765) had no effect on toxin binding. However, mutations at a neutral and an anionic site (residues 728 and 730) in S5-S6/D2 of rSkM1, which are not in the putative pore region, were found to decrease significantly the mu-CTX affinity with little effect on tetrodotoxin binding (

Dural arteriovenous fistulas involving the superior sagittal sinus: acute presentation with intracranial hemorrhage.

BACKGROUND: Intracranial dural arteriovenous fistulas (DAVF) usually drain directly into large dural venous sinuses. Intracranial hemorrhage is therefore unusual with these lesions. Certain subgroups of DAVF may drain into cortical veins causing engorgement, venous hypertension, and hemorrhage. The region of the superior sagittal sinus (SSS), while an unusual location for DAVF, is one in which drainage typically occurs directly into cortical veins. METHODS: We report on three patients with dural arteriovenous malformations of the superior sagittal sinus, all of whom presented with intracranial hemorrhage. Intraparenchymal hemorrhage in two of the cases was surrounded by excessive edema, suggesting the presence of underlying venous hypertension. RESULTS: Interventional treatment of all three of the lesions was accomplished at the time of diagnostic angiography. CONCLUSIONS: SSS DAVF is an uncommon lesion whose presentation is usually with intracranial hemorrhage. Large amounts of edema surrounding an acute hemorrhage may suggest the diagnosis, which usually requires confirmation with angiography. Treatment of SSS DAVF can often be accomplished at the time of diagnostic angiography by embolization using interventional neuroradiologic techniques. When endovascular obliteration of the fistula is not feasible or is incomplete, surgical resection of the DAVF site may be achieved without difficulty.

Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors.

A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.

Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution.

A series of P1 C alpha gem-disubstituted succinamide hydroxamate matrix metalloproteinase inhibitors were prepared stereoselectively and evaluated in vitro for their ability to inhibit MMP-1, MMP-2, and MMP-3. It was found that while methyl/allyl substitution as in 2 and 18 provided compounds that were broad spectrum inhibitors and nearly equipotent with parent inhibitor 1, a larger group such as bis-allyl as in 13 or gem-cyclopentyl as in 14 significantly reduced enzyme inhibition.

The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors.

A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.

Analysis of harvest morbidity and radiographic outcome using autograft for anterior cervical fusion.

STUDY DESIGN: Retrospective study of 184 autologous iliac crest bone grafts used for anterior cervical fusion in 144 procedures. OBJECTIVES: To evaluate the effect of autologous iliac crest bone graft harvest site on operation and recovery and to identify patients at risk for harvest morbidity. SUMMARY OF BACKGROUND DATA: Although autologous iliac crest bone graft is considered the most successful grafting material, concerns about harvest morbidity provide a rationale for considering allograft. Data about the use of autograft therefore would assist spinal surgeons in selecting the appropriate substrates for fusion after anterior cervical decompression. METHODS: Statistical analysis based on patient gender, smoking history, obesity, and medical or pharmacologic risk factors for wound healing was used to evaluate morbidity after patient interviews and examinations. Limited assessment of radiographic outcome also was performed. RESULTS: A second operation because of donor site morbidity was performed in four patients (2.8%), but only one (0.7%) with meralgia paresthetica had permanent sequelae. Superficial wound infection or dehiscence occurred in 5.6% of patients, with a disproportionate number of women, obese patients, and those with medical risk represented. Protracted wound symptoms of pain and poor cosmesis were reported in 2.8% and 3.5% of patients, respectively, and also were found in a significant number of female and obese patients. Evidence of fusion was present in 97% of cases. CONCLUSION: Autologous iliac crest bone graft harvest results in minimal major morbidity when regional anatomy is respected and careful technique is observed. The identification of patients at risk for minor complications suggests that allograft may be appropriate in these patients; however, prospective comparison is required to identify whether graft material or technical factors determine fusion success and relative benefit.

Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels.

The effects of Brazilian scorpion Tityus serrulatus toxin gamma (TiTx gamma) were studied on voltage-gated Na+ channels from human heart (hHl) and rat skeletal muscle (rSkM1). The Na+ channels were expressed in Xenopus laevis oocytes, and Na+ currents were recorded using two-microelectrode voltage-clamp techniques. In control experiments, the threshold of activation of hH1 is more negative than that of rSkM1 by approximately 20 mV. The toxin induces a shift of the voltage dependence of activation toward more negative potential values and reduces the amplitude of the current when administered to rSkM1. In contrast, TiTx gamma has little discernible effect on the current-voltage curve for hH1 at 100 nmol/L. Chimeric channels formed from these two isoforms were constructed to localize the binding site of TiTx gamma on rSkM1. TiTx gamma shifts the activation of a chimera (SSHH) in which domains 1 (D1) and 2 (D2) derive from rSkM1 and domain 3(D3) and 4 (D4) derive from hH1. This finding suggests that the toxin acts on the activation of rSkM1 by binding either to D1 and/or D2. TiTx gamma shifted the activation of another chimera with D2-D3-D4 from rSkM1 (HSSS) toward more hyperpolarizing potentials and had no effect on the activation of other chimeras with only D1-D3-D4 from rSkM1 (SHSS) or only D3 from rSkM1 (HHSH). Finally, a chimera in which D2 is from rSkM1 and all others domains are from hH1 (HSHH) provides further compelling support for our hypothesis. TiTx gamma shifts the activation of this chimera toward more negative potential values. Thus, TiTx gamma action on chimeras segregates with the source of D2: when D2 is from rSkM1, the toxin affects activation. We infer that D2 plays an important role in the activation process of voltage-gated Na+ channels.

MR of thoracic cord compression caused by epidural extramedullary hematopoiesis in myelodysplastic syndrome.

Spinal cord compression caused by extramedullary hematopoiesis is a rare complication of chronic anemic states, most frequently occurring in patients with beta-thalassemia. We report the MR appearance of extramedullary hematopoiesis resulting in cord compression in a patient with a myelodysplastic syndrome, which was isointense with the spinal cord on T1-weighted images and markedly hypointense on fast spin-echo T2-weighted images, and that demonstrated enhancement.

Assessment of spinal fusion. Critical evaluation of imaging techniques.

Before any radiologic imaging modality is employed in an investigation study, its efficacy must be critically assessed. The purpose of this report is to demonstrate how the choice of computed tomography imaging parameters affects the information provided by a computed tomographic examination. It is apparent from these results that imaging parameters must be optimized before the results of an imaging technique can be compared to other modes of diagnostic evaluation, including surgical observations.