Embryotoxicity of Five Cytostatics in Fathead Minnow (Pimephales promelas) Larvae.

Cytostatics are compounds used in chemotherapy, known to be genotoxic, mutagenic, and teratogenic at low concentrations. The amount of cytostatic drugs prescribed increases every year as does their release into the aquatic ecosystems, which possibly is a major concern for the health of aquatic organisms. This study aimed to evaluate the putative toxicity of five cytostatics to fathead minnow (Pimephales promelas) larvae: tamoxifen, capecitabine, methotrexate, cyclophosphamide, and ifosfamide. Eggs collected post-fertilization were exposed for 6 days to a range of concentrations, including one above environmental level. At all environmental concentrations, no significant difference in mortality, hatching time, length, heart rate, and presence of malformations were found. Altogether, these cytostatics do not seem embryotoxic to fish. Although, an increased proportion of complete swim bladder were found after ifosfamide's exposure, suggesting an interaction with the thyroid axis, involved in swim bladder development. Complementary work should address other endpoints, such as behavioral changes, reproductive success, and transgenerational effects.

Epidural needle insertion : A large registry analysis.

BACKGROUND: Dural puncture, paraesthesia and vascular puncture are the most common complications of epidural catheter insertion. Their association with variation in midline needle insertion depth is unknown. OBJECTIVE: This study evaluated the risk of dural and vascular punctures and the unwanted events paraesthesia and multiple skin punctures related to midline needle insertion depth. MATERIAL AND METHODS: A total of 14,503 epidural catheter insertions including lumbar (L1-L5; n = 5367), low thoracic (T7-T12, n = 8234) and upper thoracic (T1-T6, n = 902) insertions, were extracted from the German Network for Regional Anaesthesia registry between 2007 and 2015. The primary outcomes were compared with logistic regression and adjusted (adj) for confounders to determine the risk of complications/events. Results are presented as odds ratios (OR, [95% confidence interval]). MAIN RESULTS: Midline insertion depth depended on body mass index, sex, and spinal level. After adjusting for confounders increased puncture depth (cm) remained an independent risk factor for vascular puncture (adjOR 1.27 [1.09-1.47], p = 0.002) and multiple skin punctures (adjOR 1.25 [1.21-1.29], p < 0.001). In contrast, dural punctures occurred at significantly shallower depths (adjOR 0.73 [0.60-0.89], p = 0.002). Paraesthesia was unrelated to insertion depth. Body mass index and sex had no influence on paraesthesia, dural and vascular punctures. Thoracic epidural insertion was associated with a lower risk of vascular puncture than at lumbar sites (adjOR 0.39 [0.18-0.84], p = 0.02). CONCLUSION: Variation in midline insertion depth is an independent risk factor for epidural complications; however, variability precludes use of depth as a reliable guide to insertion in individual patients.

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease.

INTRODUCTION: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly ß-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. OBJECTIVE: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. METHODS: 24 CTL, 20 MCI and 19AD of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (KGlu, CMRGlu) and acetoacetate (KAcAc, CMRAcAc) were evaluated with PET using [18F]-fluorodeoxyglucose ([18F]-FDG), a glucose analogue, and [11C]-acetoacetate ([11C]-AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1-weighted MRI. RESULTS: In AD compared to CTL, CMRGlu was ~11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p<0.05). KGlu was ~15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMRAcAc or KAcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions. DISCUSSION: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.

Crohn's disease Activity: Abdominal Computed Tomography Histopathology Correlation.

PURPOSE: Crohn's disease is a type of inflammatory bowel disease affecting estimated 4 million people worldwide. Therapy stratification of Crohn's disease (CD) is mainly based on the inflammatory activity being assessed by endoscopic biopsy and clinical criteria. Cross-sectional imaging allows for the assessment of structural characteristics of the entire gastrointestinal tract including small bowel loops and may provide potential non-invasive image-based biomarkers for the inflammatory activity of CD. The aim of this study was to explore the predictive value of Computed Tomography-based morphologic patterns for inflammatory activity in CD. MATERIAL AND METHODS: 42 patients diagnosed with CD were included in a retrospective study (13 male, 29 female, median age 32 years). Abdominal CT imaging was carried out on symptomatic patients at a single institution 0-10 days prior to endoscopic biopsy or surgery using a protocol optimized for the characterization of structural bowel alterations. Image data were initially reviewed independently by three radiologists and discrepancies were settled in consensus with a focus on mesenteric fat stranding and combing, mesenteric adenopathy, mesenteric abscess, intraperitoneal free fluid, fistula, skip lesions, highest wall thickness and the localization of the affected bowel. The extent of inflammatory activity in the bowel wall was determined subsequently by histological analysis. RESULTS: All intestinal and extraintestinal CT findings except the mesenteric comb sign showed a tendency towards higher extent or prevalence in patients with high histological inflammatory activity score, especially median bowel wall thickness (6.0 mm vs. 3.5 mm), mesenteric abscesses (32% vs. 0%) and mesenteric adenopathy (94% vs. 45%). Spearman rank order correlation coefficient indicated a significant correlation of bowel wall thickness (r = 0.40, p < 0.05), mesenteric adenopathy (r = 0.54, p < 0.05), mesenteric abscess (r = 0.33, p < 0.05) and mesenteric fat stranding (r = 0.33, p < 0.05) with the histological inflammatory activity score. CONCLUSION: CT-based biomarkers including wall thickness, mesenteric fat stranding, mesenteric lymphadenopathy and mesenteric abscess positively correlated with the histological inflammatory activity score and therefore provided additional information for therapy stratification in symptomatic patients with CD, particularly as most of these biomarkers are hidden from endoscopy.

Vestibular system may provide equivalent motor actions regardless of the number of body segments involved in the task.

The vestibulospinal system likely plays an essential role in motor equivalence--the ability to reach the desired motor goal despite intentional or imposed changes in the number of body segments involved in the task. To test this hypothesis, we compared the ability of healthy subjects and patients with unilateral vestibular lesions (surgical acoustic neuroma resection 0.6 to 6.7 yr before the study) to maintain either the same hand position or the same trajectory of within arm reach movements while flexing the trunk, in the absence of vision. In randomly selected trials, the trunk motion was prevented by an electromagnetic device. Healthy subjects were able to preserve the hand position or trajectory by modifying the elbow and shoulder joint rotations in a condition-dependent way, at a minimal latency of about 60 ms after the trunk movement onset. In contrast, six of seven patients showed deficits in the compensatory angular modifications at least in one of two tasks so that 30-100% of the trunk displacement was not compensated and thus influenced the hand position or trajectory. Results suggest that vestibular influences evoked by the head motion during trunk flexion play a major role in maintaining the consistency of arm motor actions in external space despite changes in the number of body segments involved. Our findings also suggest that despite long-term plasticity in the vestibular system and related neural structures, unilateral vestibular lesion may reduce the capacity of the nervous system to achieve motor equivalence.

Effects of fast head turns on head, trunk and pelvis motions during standing and walking in patients with unilateral vestibular deficit.

Patients with unilateral vestibular deficit (UVD) report difficulties with maintaining balance while executing fast head turns. Our aim was to determine whether head, trunk, and pelvis angular displacements were symmetrical in patients with UVD as they executed voluntary yaw rotation of the head towards or away from the side of the vestibular lesion, during standing and walking. Eight patients who underwent surgical resection of an acoustic neuroma stood with feet together or walked at comfortable pace across a 10-meter walkway. They turned the head as quickly and as fast as possible in the direction indicated by an illuminating arrow (left, right or none). The head angular displacement was similar towards the affected and intact sides. Acceleration tended to be larger during head rotations towards the affected versus the intact side by 13% at the head, 42% at the trunk and 37% at the pelvis (p> 0.05, NS). The pelvis rotated opposite to the head in 65% of trials towards the affected side and 56% of the trials towards the intact side during standing and 81% and 69%, respectively during walking. Overall, the UVD had only a minor influence on the symmetry of head, trunk and pelvis kinematics during fast yaw rotation of the head executed during standing and walking.

Responses to whole head-and-body tilts with and without passive ankle dorsiflexion in the absence of visual feedback.

OBJECTIVES: We have investigated lower limb responses in seven blindfolded healthy subjects to well controlled tilts in the standing position. Our aims were (1) to determine the effect of head acceleration magnitude on responses evoked by whole head-and-body tilts, and (2) to establish whether tilt-evoked responses are modifiable by passive ankle dorsiflexion. Whole head-and-body tilts evoked responses in the biceps femoris, medial gastrocnemius and tibialis anterior muscles. METHODS: Seven young healthy subjects stood on a spring-activated tilting apparatus and underwent sudden whole head-and-body tilts of about 15 degrees from the vertical position, with or without passive ankle dorsiflexion. Head acceleration was recorded with a linear accelerometer and ankle angular displacement with a potentiometer. Surface EMG signals were recorded in the right biceps femoris, medial gastrocnemius and tibialis anterior muscles. RESULTS: As the peak of head acceleration was increased from 0.5 g to 1.8 g, the frequency of occurrence of tilt-evoked responses increased from 7% to 60% of trials in the biceps femoris muscle during whole head-and-body tilts. In general, the more proximal muscle (biceps femoris) was activated before the more distal muscle (medial gastrocnemius) during whole head-and-body tilts, while the opposite pattern was found during tilt with dorsiflexion. CONCLUSIONS: Our results indicate that the occurrence of tilt-evoked responses increases with an increase in the amplitude of tilting acceleration. This suggests that tilt-evoked responses are dependent, at least in part, on vestibular stimulation. In addition, the spatio-temporal pattern of biceps femoris and medial gastrocnemius muscle activation was opposite during whole head-and-body tilts and tilts with dorsiflexion. This finding suggests that foot/ankle somatosensory inputs can modify tilt-evoked responses.

A postural adaptation test for stroke patients.

PURPOSE: To explore the interrater reliability of the Advanced Mobility and Balance Scale (AMBS) and to determine its discriminative capacity in stroke patients. METHODS: Twelve hemiparetic patients and six healthy elderly volunteers were videotaped while: (1) executing rapid head motions during standing and walking; and (2) standing and walking on a slope. Five physical therapists viewed the videotapes to establish interrater reliability. RESULTS: Interrater reliability: Intraclass correlation ratios ranged from 0.93-0.97 for the AMBS global as well as slope and head turn subscores. Construct validity: One-way ANOVAs and post-hoc pairwise comparisons were performed to determine whether there was a difference in scores between high (HFL) and low functional-level (LFL) stroke patients (based on gait speed) and healthy subjects. Mean (+/-SD) global scores were 45 +/- 3 for healthy subjects, 40 +/- 9 for HFL stroke patients and 25 +/- 1 for LFL stroke patients (p < 0.05 for HFL versus LFL patients and LFL patients versus healthy subjects). The AMBS slope subscores were 22 +/- 2, 19 +/- 5, 9 +/- 7 for healthy, HFL and LFL subjects respectively (p < 0.05 for HFL versus LFL patients and LFL patients versus healthy subjects). CONCLUSION: The AMBS has excellent interrater reliability and good discriminative capacities.

Rhythmical eye-head-torso rotation alters fore-aft head stabilization during treadmill locomotion in humans.

A repetitive manoeuvre called torso rotation (TR) is known to temporarily reduce the gain of the horizontal vestibulo-ocular reflex by 10-15% in healthy humans. TR consists of a series of rhythmical rotations of the eyes, head and upper body executed continuously for 30 minutes while standing. Our aim was to investigate whether TR affects the ability to hold the head in a fixed fore-aft position relative to space while walking on a treadmill with eyes closed. Ten healthy subjects stood in a carefully standardized position on a stationary treadmill. The treadmill started unexpectedly and ran for 4 s at 29 cm/s. The test stimulus was a linear acceleration in the fore-aft direction at the moment of treadmill start-up. Linear head position (i.e., ability to stabilize the head) was measured during and following the stimulus. A mechanical system prevented head rotation. Two series of 60 trials were performed before TR (control 1 and control 2 series) and one after TR. Before TR, subjects drifted rearward at an average drift velocity +/- S.D. = 3.1 +/- 0.9 cm/s. This drift was reasonably stable over time within and between the two control series. After TR, head holding ability was further impaired, with subjects having more difficulty to stabilize their head after treadmill start-up. In the first 10 trials after the arrest of TR, the average drift velocity was significantly larger than before TR(6.1 +/- 1.5 cm/sec, p < 0.01). Recovery to control values followed a roughly exponential time course, with 67% recovery occurring in the first 3.4 minutes after TR. Our results indicate that TR impairs the ability to sense and/or respond to fore-aft linear accelerations of the head following treadmill start-up in the absence of vision.

Reflex interactions during whole head-and-body tilts are modified by age in humans.

We have demonstrated that lower limb extensor muscle response to tibial nerve stimulation is significantly facilitated by whole head-and-body tilt in the forward direction. Our aim was to examine whether this reflex interaction is influenced by age. Reflexes were elicited in lower limb muscles by electrical stimulation (ES) of the right tibial nerve. We compared reflexes during supported stance (ESalone) and sudden forward tilting of the whole head-and-body (Tilt+ES) between 10 healthy subjects aged 66 +/- 4 years and 13 subjects aged 27 +/- 3 years. In young subjects the area of response evoked in the ipsilateral vastus lateralis (iVL) was significantly increased by 74% during Tilt+ES as compared with ESalone (p < 0.05). Moreover, the latency of contralateral VL and soleus muscle responses (cVL and/or cSO) was significantly shorter by 61 ms during Tilt+ES than ESalone (p < 0.01). In contrast, older subjects showed no significant increase in the excitability of iVL muscle response and cVL and/or cSO muscle responses during Tilt+ES as compared with ESalone, despite the application of similar intensity of ES and head acceleration as in young subjects. Our findings showed that the interaction between ES-evoked and tilt-evoked responses in lower limb extensor muscles is modified with age, which suggests modifications of sensorimotor integration involved in balance control.

Human soleus H-reflex excitability is decreased by dynamic head-and-body tilts.

The modulation of soleus (SO) H-reflex excitability during dynamic whole head-and-body tilts (WHBT) was investigated in normal healthy subjects. Between 30 and 70 ms, and 151 and 190 ms after head acceleration onset, the H-reflex amplitude was smaller than during quiet standing by 7.6% (p < 0.01) and 15.4% (p = 0.06) respectively. This finding suggested that dynamic WHBT reduced the excitability of the predominantly monosynaptic stretch reflex are in the majority of the subjects studied.

Responses to dynamic head-and-body tilts are enhanced in Parkinson's disease.

BACKGROUND: Previous studies demonstrated that destabilizing responses to slow perturbations were enhanced in patients with Parkinson's disease (PD). Our objectives were to investigate the influence of PD on responses to faster whole head-and-body tilts in the standing position, and to establish whether any modification of tilt-evoked responses in PD patients was related to possible changes in the modulation of soleus (SO) H-reflex. METHODS: Ten PD patients and 10 age-matched normal subjects assumed a standing position on an L-shaped tilting apparatus. Their head and shoulders were firmly attached to the back support of the apparatus, while their feet were fixated to the standing platform. With their vision occluded, the subjects's whole head-and-body was suddenly tilted forward to 20 degrees, at a peak head acceleration of 0.7 g +/- 0.1 g. Tilt-evoked responses were recorded from the lower limb muscles bilaterally. In addition, 40 H-reflexes were elicited in the SO muscle at 30-190 ms intervals after the onset of head acceleration. The M response amplitude was kept within +/- 15% of its control value. RESULTS: PD patients demonstrated an abnormally high responsiveness to whole head-and-body tilts in comparison with age-matched normal subjects. This was shown by the significantly larger proportion of PD patients manifesting responses in the SO, biceps femoris and vastus lateralis muscles (p < 0.05), as well as their significantly larger SO response area (413%; p < 0.01). In contrast, the amplitude of the SO H-reflex was significantly increased by only 14% (p < 0.05) in these patients, and only at 30-70 ms after head acceleration onset. CONCLUSIONS: The overexcitable tilt-evoked responses of PD patients could originate from a reduced ability to suppress responses when the body is supported. This enhanced excitability of tilt-evoked responses was probably not due to motoneuronal hyperexcitability or decreased presynaptic inhibition of the group Ia terminals involved in the mainly monosynaptic H-reflex pathway. Thus, we hypothesize that the control of spinal interneurons involved in the tilt-evoked responses may be defective in PD.

Extensor muscle responses to tibial nerve stimulation are enhanced during dynamic tilts in standing humans.

We studied the interaction between muscle responses evoked in standing by electrical stimulation (ES) of the tibial nerve and dynamic tilts of the head-and-body in 13 young healthy subjects. Subjects were attached to an L-shaped tilting apparatus and underwent sudden forward tilting of their head-and-body as a whole, without ankle rotation. During such tilts, the area of response evoked in the ipsilateral vastus lateralis (iVL) muscle by the ES was significantly increased by 74% as compared to quiet supported stance (P = 0.01). The response latency of the contralateral VL and soleus muscles i.e. the crossed extension reflex, was significantly shorter during tilt (54 +/- 22 ms) than during quiet supported stance (115 +/- 13 ms, P < 0.01). The increased excitability of extensor muscles activated by ES during tilt seems appropriate to maintain stance during a forward perturbation of the body.

Functional modulation of the human flexion and crossed extension reflexes by body position.

The effects of body position on the electrically evoked flexion (FR) and crossed extension reflexes (CER) were investigated in humans. The FR area in the ipsilateral tibialis anterior muscle was significantly smaller during sitting than supported stance by 36% (P < 0.01). In contrast, the excitability of extensor muscles on both sides was enhanced in standing. For instance, twice as many subjects manifested a response in the ipsilateral vastus lateralis (VL) and the contralateral VL and/or soleus muscles (i.e. the CER) in standing than sitting. The FR and CER modulation observed seems to be dictated by the difference in functional demand between sitting and supported stance.

False-positive 201thallium study in Wolff-Parkinson-White syndrome.

Wolff-Parkinson-White syndrome (WPW) is known to cause abnormal rest electrocardiogram and stress tests. Consequently, the diagnosis of coronary artery disease (CAD) may be difficult in patients with WPW. Previous reports have described false positive stress 201thallium studies in WPW, but the absence of CAD has rarely been confirmed by coronary angiography. A case of false positive stress 201thallium scintigraphy confirmed by angiography is presented. Left ventricular contractile asynchrony can explain the defects observed in myocardial perfusion scintigraphy. The importance of the defects relates to the length of the delta wave.

cDNA cloning of a human 100 kDa de-ubiquitinating enzyme: the 100 kDa human de-ubiquitinase belongs to the ubiquitin C-terminal hydrolase family 2 (UCH2).

The full length cDNA encoding a 100 kDa human de-ubiquitinating enzyme, referred to as de-ubiquitinase was obtained using one clone selected from a randomly sequenced human brain cDNA library and specific primers. The sequence of 18 peptides generated from the de-ubiquitinase isolated from out-dated human erythrocytes matched perfectly with the predicted amino acid sequence, which would encode a protein containing 858 amino acids (calculated M(r) = 95,743 Da). Homology search disclosed that the protein is a member of a large family of ubiquitin C-terminal hydrolases (UCH2), that was defined on the basis of the presence of two specific patterns, 'the Cys- and His-domains', which are likely to be involved in the de-ubiquitinating activity [7]. An additional conserved region, 'the aspartic acid domain', was also identified, the functional role of which is unknown.

Structural characterization and expression of the human dehydroepiandrosterone sulfotransferase gene.

Dehydroepiandrosterone sulfotransferase catalyzes the transformation of dehydroepiandrosterone to dehydroepiandrosterone sulfate, the most abundant steroid in circulation in the human and primate. Dehydroepiandrosterone sulfate serves as precursor for the formation of active androgens and estrogens in peripheral target tissues. In addition, blockade at the dehydroepiandrosterone level could give raise to high level of DHEA and thus disorders due to mild excess of androgen. Recently, the cDNA encoding dehydroepiandrosterone sulfotransferase has been isolated from a human liver cDNA library. To study the regulation and expression, as well as the possible defect linked to DHEA sulfotransferase gene, we have isolated and characterized its structure by screening a lambda EMBL3 library of human leukocyte genomic DNA using human dehydroepiandrosterone sulfotransferase cDNA as a probe. Sequencing of the gene shows that it is included in approximately 17 kb and contains six exons separated by five introns. Northern blot analysis shows a strong signal in the adrenals and liver, whereas no signal was detected in the spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, heart, brain, placenta, lung, skeletal muscle, kidney, or pancreas. Using primer extension analysis, the transcription start site is located at nucleotide 98 upstream from the ATG initiating codon. Putative TATA and CAAT boxes are situated at positions 72 and 96 upstream from the transcription start site, respectively. Using DNA from a panel of human/rodent somatic cell hybrids, and amplification of the gene by the polymerase chain reaction, the human dehydroepiandrosterone sulfotransferase gene has been assigned to chromosome 19.

A spring-activated tilting apparatus for the study of balance control in man.

A tilting apparatus has been designed and constructed to produce fore-aft whole head-and-body tilt (WHBT) alone, or in combination with ankle dorsiflexion of standing subjects, about an axis colinear with the ankle joint. The apparatus is composed of a vertical tilting structure attached to a supporting base. Mechanical rotation of the vertical tilting structure is achieved by a spring activating system mounted on its base. Subjects are secured to the vertical structure by a body harness system with the head fixed, and the feet secured to the standing platform. Simultaneous dynamic WHBT and ankle joint displacement are induced by rotating the vertical support; whereas WHBT alone is achieved by concurrent rotation of both the vertical support and standing platform. Tilts are triggered manually, and data acquisition precedes head acceleration onset by 50-100 ms to provide suitable baseline values. This tilting apparatus has been successfully used to apply forward WHBT in 34 subjects with height ranging from 1.55 to 1.87 m and weights from 42 to 95 kg, and at magnitudes of peak head acceleration varying from 0.4 to 2.2 g as measured by a linear accelerometer mounted on a dental bite. These acceleration rates can be reproduced with minor variation in the same subjects. Moreover, the area under the head acceleration traces was reproducible within 15% between subjects. Tilts can be delivered with concomitant ankle dorsiflexion. These features make the low-cost tilting apparatus a very useful tool for the study of human tilting reactions in both laboratories and clinical settings.

A human de-ubiquitinating enzyme with both isopeptidase and peptidase activities in vitro.

Some enzymatic and physicochemical properties of a human ubiquitin-specific isopeptidase are reported. The enzyme was purified to homogeneity from red blood cells and its specificity towards polymeric ubiquitin substrates suggests a de-ubiquitinating activity capable of cleaving 'head-to-tail' polyUb chains as well as isoamide 'branched' Ub dimers. KM values show a 10 fold preference for the cleavage of branched Ub dimers over head-to-tail Ub dimers. The enzymatic activity can be strongly inhibited by various peptides containing either of the cleavage site sequences found in Ub polymers, but not by unrelated peptides. The enzyme is monomeric under reducing conditions and exhibits a globular shape with an average diameter of 9 nm, an S20,w value of 5.2 S and a molar mass of 110 kDa +/- 10%. Because the enzyme cleaves both peptide-linked and isopeptide-linked Ub moieties from substrates, we propose to name it de-ubiquitinase rather than isopeptidase.