Battery longevity of neurostimulators in Parkinson disease: A historic cohort study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for motor complications in Parkinson disease (PD). Since 2012, the nonrechargeable dual-channel neurostimulator available in France seems to have shorter battery longevity compared to the same manufacturer's previous model. OBJECTIVE: The aim of this study was to evaluate the battery longevity of older and more recent neurostimulators from the same manufacturer and to explore factors associated with battery life variations. MATERIALS AND METHODS: We retrospectively studied our cohort of PD patients who underwent STN DBS between 1987 and 2017. We collected data concerning neurostimulator replacements and parameters. We compared the survival of the first device available, Kinetra® and the current one, Activa-PC® (Medtronic Inc.) and estimated the factors that had an impact on battery longevity through a Cox logistic regression. RESULTS: Three hundred sixty-four PD patients received a total of 654 DBS STN neurostimulators: 317 Kinetra® and 337 Activa-PC®. The survival analysis, using the Kaplan-Meier estimator, showed a difference between the curves of the two devices (log-rank test; p < 0.001). The median survival of an Activa-PC® neurostimulator was 1666 days, while it was 2379 days for a Kinetra®. After adjustment, according to the multivariate analysis, the main factors associated with battery lifetime were: the neurostimulator type; the number of subsequent neurostimulator implantations; the total electrical energy delivered (TEED); and sex. CONCLUSION: The Kinetra® neurostimulator lifetime is 2.5 years longer than the Activa-PC®. The type of the device, the high TEED and the number of subsequent neurostimulator implantations influence battery longevity most. These results have medical-economic implications since the survival of PD patients with DBS increases over years.

Generalization of ionic partition diagrams to lipophilic compounds and to biphasic systems with variable phase volume ratios.

The ionic partition diagram methodology has been generalized to address both hydrophilic and lipophilic compounds and to consider biphasic systems with variable phase volume ratios. With this generalized approach electrochemical measurements of ion transfer potentials afford the determination of the standard partition coefficients of all forms of ionizable molecules, including the neutral form, as well as the evaluation of the dissociation constant of monoprotic substances. An interesting consequence of this approach is the definition of an extraction pK(a,ext) which is the apparent pK(a) of neutral acids and bases when dissolved in the organic phase.

The F-box protein Skp2 is a ubiquitylation target of a Cul1-based core ubiquitin ligase complex: evidence for a role of Cul1 in the suppression of Skp2 expression in quiescent fibroblasts.

The ubiquitin protein ligase SCF(Skp2) is composed of Skp1, Cul1, Roc1/Rbx1 and the F-box protein Skp2, the substrate-recognition subunit. Levels of Skp2 decrease as cells exit the cell cycle and increase as cells re-enter the cycle. Ectopic expression of Skp2 in quiescent fibroblasts causes mitogen-independent S-phase entry. Hence, mechanisms must exist for limiting Skp2 protein expression during the G(0)/G(1) phases. Here we show that Skp2 is degraded by the proteasome in G(0)/G(1) and is stabilized when cells re-enter the cell cycle. Rapid degradation of Skp2 in quiescent cells depends on Skp2 sequences that contribute to Cul1 binding and interference with endogenous Cul1 function in serum-deprived cells induces Skp2 expression. Furthermore, recombinant Cul1-Roc1/Rbx1-Skp1 complexes can catalyse Skp2 ubiquitylation in vitro. These results suggest that degradation of Skp2 in G(0)/G(1) is mediated, at least in part, by an autocatalytic mechanism involving a Skp2-bound Cul1-based core ubiquitin ligase and imply a role for this mechanism in the suppression of SCF(Skp2) ubiquitin protein ligase function during the G(0)/G(1) phases of the cell cycle.

Association of human ubiquitin-conjugating enzyme CDC34 with the mitotic spindle in anaphase.

Present in organisms ranging from yeast to man, homologues of the Saccharomyces cerevisiae ubiquitin-conjugating enzyme CDC34 have been shown to play important roles in the regulation of cell cycle progression and checkpoint function. Here we analyze the expression and intracellular localization of endogenous CDC34 during mammalian cell cycle progression. We find that CDC34 protein is constitutively expressed during all stages of the cell cycle. Immunofluorescence experiments reveal that during interphase, endogenous CDC34 is localized to distinct speckles in both the nucleus and the cytoplasm. The presence of CDC34 in these compartments has also been established by biochemical fractionation experiments. Interestingly, nuclear localization depends on the presence of specific carboxy-terminal CDC34 sequences that have previously been shown to be required for CDC34's cell cycle function in Saccharomyces cerevisiae. Finally, we find that in anaphase and not during early stages of mitosis, CDC34 colocalizes with (beta)-tubulin at the mitotic spindle, implying that it may contribute to spindle function at later stages of mitosis. Taken together, these results support a model in which CDC34 ubiquitin-conjugating enzyme functions in the regulation of nuclear and cytoplasmic activities as well as in the process of chromosome segregation at the onset of anaphase in mammalian cells.

Combined molecular lipophilicity descriptors and their role in understanding intramolecular effects.

Traditional lipophilicity parameters (log P and log D) are well-known physico-chemical descriptors largely used in QSAR studies. Besides their numerical value, log P data contain a variety of information about inter- and intramolecular forces affecting partitioning and its related biological phenomena. The deconvolution of information from log P can be accessed only by adequate interpretative tools, such as new lipophilic-combined descriptors, of which features and some applications are presented in this review.

The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis.

PURPOSE: The anti-ischemic drug trimetazidine (TMZ) acts by a combination of molecular mechanisms which begin to be understood. Thus, it acts in the micromolar range to significantly reduce intracellular acidification during ischemia. To search for a possible physicochemical explanation of this phenomenon, we investigated the transfer mechanisms of the various electrical forms of this dibasic drug. METHODS: The transfer characteristics of TMZ were studied by electrochemistry at the water/1,2-dichloroethane interface. Cyclic voltammetry was used to measure the formal transfer potentials of singly and doubly protonated forms of TMZ (noted TH+ and TH(2)2+, respectively) as a function of aqueous pH, and the partition coefficient of neutral TMZ (log P(T)) was measured by two-phase titration. RESULTS: log P(T) was measured to be 1.04 +/- 0.06, and the acid-base dissociation constants in water were deduced to be pK(w)a1 = 4.54 +/- .02 and pK(w)a2 = 9.14 +/- 0.02. The partition coefficients of TH+ and TH(2)2+ were found to be respectively log P0'TH+ = -3.78 +/- 0.16 and log P0'TH(2)2+ = -9.84 +/- 0.30, which agrees well with the charge being delocalized on two nitrogen atoms in TH+. The pH-partition profile of TMZ was then established in the form of its ionic partition diagram, which showed that the affinity of the ions for the organic phase is pH-dependent and strongly increased by the interfacial potential. CONCLUSIONS: This behavior suggests a physicochemical mechanism whereby efflux of protonated TMZ out of an acidified cell is facilitated, in effect exporting protons to extracellular space.

Microchannel networks for electrophoretic separations.

UV excimer laser photoablation was used to micro-machine polymer substrates not only to drill microchannel structures but also to change the surface physical properties of the substrates. We first describe how UV laser photoablation can be used for the patterning of biomolecules on a polymer and discuss parameters such as surface coverage of active antibodies and equilibration time. Secondly, we show how to design a single-use capillary electrophoresis system comprising an on-chip injector, column and electrochemical detector. The potential of this disposable plastic device is discussed and briefly compared to classical systems. Finally, preliminary results on protein separation by isoelectric focusing on a disposable microchip are presented.

Radiographic measurement of alveolar bone loss in the living rat.

We describe a method which allows longitudinal measurements of alveolar bone loss in the living rat. The anesthetized animal is kept in a fixed and reproducible position and radiographs of an upper molar arch are taken with a mammography. In a preliminary study, 4 rats were repeatedly radiographed. In the main study, 10 rats were radiographed at day 0 and after 63 days of diet known to cause periodontitis. The radiographs were enlarged and the amount of bone lost calculated by comparing the weights of the interdental areas reproduced on standard paper. In the preliminary study, the coefficient of variation (C.V.) of the average weights of paper were fairly low (4 to 9%) in the first 3 rats, and amounted to 17% in the fourth. A statistically significant average loss of bone (16%) was found in the 10 rats in the main study when comparing the weights of papers at days 0 and 63.

trans-Golgi retention of a plasma membrane protein: mutations in the cytoplasmic domain of the asialoglycoprotein receptor subunit H1 result in trans-Golgi retention.

Unlike the wild-type asialoglycoprotein receptor subunit H1 which is transported to the cell surface, endocytosed and recycled, a mutant lacking residues 4-33 of the 40-amino acid cytoplasmic domain was found to be retained intracellularly upon expression in different cell lines. The mutant protein accumulated in the trans-Golgi, as judged from the acquisition of trans-Golgi-specific modifications of the protein and from the immunofluorescence staining pattern. It was localized to juxtanuclear, tubular structures that were also stained by antibodies against galactosyltransferase and gamma-adaptin. The results of further mutagenesis in the cytoplasmic domain indicated that the size rather than the specific sequence of the cytoplasmic domain determines whether H1 is retained in the trans-Golgi or transported to the cell surface. Truncation to less than 17 residues resulted in retention, and extension of a truncated tail by an unrelated sequence restored surface transport. The transmembrane segment of H1 was not sufficient for retention of a reporter molecule and it could be replaced by an artificial apolar sequence without affecting Golgi localization. The cytoplasmic domain thus appears to inhibit interaction(s) of the exoplasmic portion of H1 with trans-Golgi component(s) for example by steric hindrance or by changing the positioning of the protein in the membrane. This mechanism may also be functional in other proteins.

Cloning and sequence analysis of rat hepsin, a cell surface serine proteinase.

A cDNA coding for the rat serine proteinase hepsin was isolated and its nucleotide sequence has been determined. The cDNA was 1739 nucleotides long and contained an open reading frame encoding a protein consisting of 416 amino-acid residues. The deduced amino-acid sequence of the rat enzyme was very similar to the human hepsin sharing an amino-acid sequence identity of 88.7%. Hydropathy plots reveal the presence of a short hydrophobic region close to the N-terminus believed to be a transmembrane domain which anchors the proteinase on the cell surface. The predicted sequence contains the His, Asp and Ser residues which make up the catalytic triad common to all serine proteinases.

Thyrotropin action is impaired in the thyroid gland of old rats.

Aging in rats is characterized by low plasma concentrations of thyroid hormones with unchanged levels of TSH, suggesting an altered TSH action in addition to the impaired regulation of TSH secretion. To evaluate TSH action we determined TSH binding to thyroid membranes of young and old male rats (3-4 and 24-26 months of age), as well as the activity of adenylate cyclase in basal and stimulated conditions. Saturation analyses of [125I]-bTSH to thyroid membranes in the presence of increasing quantities of unlabelled bTSH (0.03-100 mU) show two types of binding sites, one of high affinity (Ka 1.5 10(9) mol l-1) the other of lower affinity (Ka 1.2 10(8) mol l-1), which are similar in both age groups. The number of TSH binding sites of high affinity is less in old rats than in young rats (7.6 +/- 0.9 vs 14.8 +/- 1.1 TSH mU/mg protein, N = 11 and 10 respectively, p less than 0.001), whereas the number of binding sites of low affinity is not significantly different (76.0 +/- 8.2 vs 99.1 +/- 9.0 TSH mU/mg protein). The activity of adenylate cyclase determined in basal conditions is similar in both old and young rats (1.11 +/- 0.12 vs 1.04 +/- 0.9 nmol cAMP/2 h x mg/protein). TSH (10 mU) induced a significant increase in cAMP formation with the thyroid membranes from young rats but not with those from old rats. In contrast, the stimulation of cAMP formation by GTP (2 mmol/l) or forskolin (10 mmol/l), two direct stimulators of adenylate cyclase, is similar in both groups of rats (200% and 250%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Sex steroids modulate the pituitary parameters involved in the regulation of TSH secretion in the rat.

The sex-related differences observed in the regulation of TSH secretion was further investigated by determination of the densities of T3 nuclear and TRH membrane receptors as well as the activity of 5'-deiodinase (5'D) in the anterior pituitary gland of adult male and female rats. The respective modulatory roles of androgens and estrogens on these parameters were evaluated by similar determinations carried out in castrated and in estrogen-treated male rats. The density of pituitary T3 and TRH receptors and the activity of 5'D type II were significantly greater in the female than in the male rats. The E2-treated male rats disclosed a female profile, viz. also greater densities of T3 and TRH receptors when compared with control male rats (2.3 +/- 0.2 vs 1.8 +/- 0.2 fmol T3/mg gland and 9.4 +/- 0.8 vs 6.0 +/- 0.8 fmol TRH/mg gland, mean +/- SEM), whereas no changes were found in the castrated rats. The E2-treated rats and the castrated rats exhibited an increased pituitary activity of 5'D, type II (0.87 +/- 0.10 and 0.66 +/- 0.05, respectively, vs control 0.34 +/- 0.07 pmol rT3.h-1.(mg protein)-1), suggestive of a stimulatory effect of E2 and of an inhibitory effect of androgens on this parameter. In contrast, no differences in hepatic 5'D were found between all groups, illustrating the well-known tissue-specific regulation of 5'D. These results demonstrate that the sex difference in the density of pituitary T3 and TRH receptors and the activity of 5'D in the adult rat is mainly due to a modulatory effect of estrogens, which may be responsible for the sex-dependent regulation of TSH secretion.

[Incidence of polyneuropathies in chronic obstructive bronchopneumopathies]. / Fréquence des polyneuropathies dans les bronchopneumopathies chroniques obstructives.

In a prospective study 43 patients with chronic obstructive lung disease and severe respiratory insufficiency were systematically investigated for polyneuropathy, although they had no risk factor of that disease. Electrophysiological recordings showed slight or significant signs of polyneuropathy in 17 and 15 patients respectively, thus indicating that the condition is frequent. Clinically, it was often silent or manifested only by sensory disorders predominant in the lower limbs. Electrophysiology suggested axonal degeneration associated with some degree of demyelinization, and these lesions were found at histology to be present in sensory nerves. Histological examination of the muscles showed peripheral mixed neurogenic atrophy probably due to hypoxia. Major thickening of basal material was observed in capillaries of the endomysium and endoneurium. Statistical analysis of clinical parameters and respiratory function values in relation to the presence and importance of polyneuropathy showed that the only significant difference was the longer duration of hypoxia in patients with nerve involvement. Age, alcoholism and the other respiratory function values did not seem to be correlated with lesions of the peripheral nervous system.

[Neuropathies and chronic respiratory insufficiency: electrophysiologic study]. / Neuropathies et insuffiscance respiratoire chronique: étude électrophysiologique.

In order to determine the frequency and the characteristics of neuropathies in chronic respiratory insufficiency, a systematic study of 43 patients affected by a chronic obstructive pulmonary disease was performed. In addition to neurological and electrophysiological examinations (including 6 nerve conduction studies on median, ulnar and peroneal nerves and EMG of 4 to 8 muscles), nerve and muscle biopsies (of the superficial peroneal nerve and lateral peroneus brevis muscle) were performed in 13 cases. Polyneuropathies were found in 74% patients: but mild in 39%, severe in 35%. Most were subclinical or poorly symptomatic. We determined the importance and distribution of abnormalities on the different nerves. From this we established that neuropathies are mixed but predominantly of the axonal type. Axonal degeneration and demyelination were confirmed by nerve biopsy; muscles presented neurogenic atrophy. Statistical analysis showed that the duration of hypoxemia was related to neuropathy. The pathogeny of these neuropathies is discussed.