Cracking the neural code, treating paralysis and the future of bioelectronic medicine.

The human nervous system is a vast network carrying not only sensory and movement information, but also information to and from our organs, intimately linking it to our overall health. Scientists and engineers have been working for decades to tap into this network and 'crack the neural code' by decoding neural signals and learning how to 'speak' the language of the nervous system. Progress has been made in developing neural decoding methods to decipher brain activity and bioelectronic technologies to treat rheumatoid arthritis, paralysis, epilepsy and for diagnosing brain-related diseases such as Parkinson's and Alzheimer's disease. In a recent first-in-human study involving paralysis, a paralysed male study participant regained movement in his hand, years after his injury, through the use of a bioelectronic neural bypass. This work combined neural decoding and neurostimulation methods to translate and re-route signals around damaged neural pathways within the central nervous system. By extending these methods to decipher neural messages in the peripheral nervous system, status information from our bodily functions and specific organs could be gained. This, one day, could allow real-time diagnostics to be performed to give us a deeper insight into a patient's condition, or potentially even predict disease or allow early diagnosis. The future of bioelectronic medicine is extremely bright and is wide open as new diagnostic and treatment options are developed for patients around the world.

Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients.

Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an iron­sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery. Disorders in the ISC machinery affect numerous Fe-S proteins and lead to a heterogeneous group of diseases with a wide variety of clinical symptoms and combined enzymatic defects. Here, we present the biochemical profiles of several key mitochondrial [Fe-S]-containing proteins in fibroblasts from 13 patients carrying mutations in genes encoding proteins involved in either the lipoic acid (LIPT1 and LIPT2) or mitochondrial ISC biogenesis (FDX1L, ISCA2, IBA57, NFU1, BOLA3) pathway. Ten of them are new patients described for the first time. We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype. We find that oxidative phosphorylation can be affected by LA defects in LIPT1 and LIPT2 patients due to excessive oxidative stress or to another mechanism connecting LA and respiratory chain activity. We confirm that NFU1, BOLA3, ISCA2 and IBA57 operate in the maturation of [4Fe-4S] clusters and not in [2Fe-2S] protein maturation. Our work suggests a functional difference between IBA57 and other proteins involved in maturation of [Fe-S] proteins. IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3. Finally, our study establishes different biochemical profiles for patients according to their mutated protein.

Evolution of psychosocial factors at work in a French region.

BACKGROUND: Psychosocial factors at work (PFW) can be defined as all non-physicochemical occupational risks. Several epidemiological models have been proposed to measure PFW, but one of the most widely used is Karasek's model. AIMS: To determine whether psychosocial factors, evaluated by Karasek's questionnaire, had increased in a cohort of workers. METHODS: A random sample of workers in the Pays de la Loire region of France, who could be considered representative of the region's population of salaried workers, filled in a self-administered questionnaire, including Karasek's self-administered questionnaire, in 2002-05 and 2007-09. Karasek's questionnaire can be used to study three psychosocial dimensions (psychological demand, decision latitude and social support in the workplace) in workers in order to define two high-risk situations for their health: 'Job Strain' and 'Iso Strain'. Changes in job strain and iso strain among workers were studied according to the workers' sociodemographic characteristics and their working conditions. RESULTS: In this sample of 2049 workers, the proportion with iso strain increased between the two periods from 12 to 16%, P < 0.001, mainly among manual workers. Deterioration of Karasek indicators was mainly explained by an increase of the 'low social support' dimension (38 versus 49%, P < 0.001). Working conditions such as temporary employment of colleagues and high perceived physical exertion were associated with higher PFW. CONCLUSIONS: This study, based on a quantitative and collective model, showed deterioration of working team environments and increased risk for individual mental health in this cohort of French workers in recent years.

Polymer formulated self-amplifying RNA vaccine is partially protective against influenza virus infection in ferrets.

COVID-19 has demonstrated the power of RNA vaccines as part of a pandemic response toolkit. Another virus with pandemic potential is influenza. Further development of RNA vaccines in advance of a future influenza pandemic will save time and lives. As RNA vaccines require formulation to enter cells and induce antigen expression, the aim of this study was to investigate the impact of a recently developed bioreducible cationic polymer, pABOL for the delivery of a self-amplifying RNA (saRNA) vaccine for seasonal influenza virus in mice and ferrets. Mice and ferrets were immunized with pABOL formulated saRNA vaccines expressing either haemagglutinin (HA) from H1N1 or H3N2 influenza virus in a prime boost regime. Antibody responses, both binding and functional were measured in serum after immunization. Animals were then challenged with a matched influenza virus either directly by intranasal inoculation or in a contact transmission model. While highly immunogenic in mice, pABOL-formulated saRNA led to variable responses in ferrets. Animals that responded to the vaccine with higher levels of influenza virus-specific neutralizing antibodies were more protected against influenza virus infection. pABOL-formulated saRNA is immunogenic in ferrets, but further optimization of RNA vaccine formulation and constructs is required to increase the quality and quantity of the antibody response to the vaccine.

A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve.

OBJECTIVE: Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible 'microelectrode' array, for recording and stimulation of the mouse vagus nerve. APPROACH: The array was microfabricated on an 8 µm layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. MAIN RESULTS: Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1ß), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. SIGNIFICANCE: This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice.

[Effect of the antioxidants on NO-dependent induction of heme oxigenase 1 gene in U937 monocytes].

Previously it was shown that thiol antioxidants are potent inhibitors of the NO-dependent induction of heme oxygenase 1 (HOX-1) gene. However, the mechanism of HOX-1 gene down-regulation by thiol antioxidants and underlying signaling pathway remain unclear. In this study we have examined, whether the scavenging of reactive oxygen and reactive nitrogen species (ROS and RNS) is the major cause for thiol-mediated suppression of the HOX-1 induction by NO. Further, to identify the ROS family members implicated in the HOX-1 induction, we also exposed cells to various non-thiol antioxidants: dimethyl sulfoxide, dimetylthiourea, sodium salicylate, sodium formate, uric acid, catalase, and superoxide dismutase. A partial inhibition of HOX-1 induction occurred in the presence of non-polar hydroxyl radical scavengers, dimethyl sulfoxide and dimetylthiourea. The other non-thiol antioxidants were ineffective towards HOX-1 expression. Then, in order to determine, whether RNS scavenging is implicated in the HOX-1 down-regulation by thiol antioxidants, we took advantage of the capacity of suboptimal concentrations of the NO scavenger PTIO (2-phenyl-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide) to oxidize NO to nitrosating species. We showed that simultaneous cell treatment with NO donor and PTIO significantly enhanced the rate of the HOX-1 gene NO-dependent induction indicating that RNS are mediators of HOX-1 gene transcriptional activation. Thiol antioxidants completely suppressed PTIO stimulatory action. These findings imply that inhibitory action of thiol antioxidants is mediated by RNS scavenging. The study provides an approach for pharmacologycal modulation of cell response to NO and its derivatives through the use of antioxidants.

Effects of lead on gene expression.

Lead poisoning is a worldwide, environmental health-hazard that affects children and adults. In this review we discuss the effects of lead on gene expression due to both general and specific mechanisms. In particular we focus on the ability of lead to substitute for biologically essential metals such as calcium and zinc in metal-binding domains of cytoplasmic enzymes, nuclear transcription factors and other proteins. The binding of lead to these proteins causes an alteration of their activity resulting in aberrant expression of their own genes and in some cases their target genes. Finally, we discuss the impact of microarray technology on the study of the genome-wide effects of lead and other toxicants on gene expression.

Lymph node modification in patients with the acquired immunodeficiency syndrome (AIDS) or with AIDS related complex (ARC). A histological, immuno-histopathological and ultrastructural study of 45 cases.

The authors present the results of a histopathological study on the lymph-nodes taken from 45 subjects suffering from either an AIDS or from a chronic adenopathy corresponding to the definition of AIDS related complex (ARC). The various aspects observed were classed as type I to type IV. The lymph-node modifications observed in the 29 patients with an ARC could be divided into three principle groups: an extensive follicular hyperplasia associated with other elementary lesions or type IA (25 lymph-nodes from 23 patients); changes resembling a multicentric Castleman syndrome or type IB (1 case); angioimmunoblastic-like (AIL) lesions or type II (2 cases) and an association of lesions of type II (7 lymph-nodes from 6 patients). During AIDS, the adenopathy usually disappears, and the small lymph-nodes removed, especially on autopsy, show an extensive lymphoid depletion (type III) with systematic sclerosis (15 lymph-nodes from 14 patients). When adenopathy persists, it is due to infections complications (tuberculosis, cryptococcosis, avian mycobacteriosis and Whipple's disease like lesions). Of the 10 patients in whom a Kaposi's sarcoma was observed, only 6 showed lymph-node involvement, or type IV. The different histopathological lesions seem to appear according to an evolving succession, proven by certain association of lesions and by successive biopsies. In our series, 17% of subjects with an ARC evolved to AIDS. Lymph-node biopsy allows a possible ARC to be implicated on the association of the following simple lesions: follicular hyperplasia with partial or total destruction of the perifollicular lymphocytic cisterna, infiltration of the germinative centres by streams of small lymphocytes, evolving to an aspect of a "burst" germinative centre and various sinusal reactions with, in particular, the presence of neutrophilic polynuclear cells. The biopsy also allows the forms with bad prognosis to be recognized: those with AIL-like aspect or multicentric Castleman-like syndrome, which seems to represent a particular evolutive form. Finally, it also detects, in certain cases, the localization of a Kaposi syndrome, signalling the passage to AIDS. The immunopathological studies present a double interest. Firstly, they offer arguments in favour of the diagnosis: increase in the number of T8 lymphocytes in the germinative centres with the formation of small clusters and disruption of the network of dendritic reticular cells, and the inversion of the T4/T8 ratio in the extra-follicular cortical regions, by either a decrease in T4 lymphocytes or by an increase in T8 lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

The discovery of the physical basis of language during the eighteenth century in Europe.

Reflection about the relationship between language and body has a long history. In spite of the fact that for centuries the most audacious thinkers and philosophers have established a close link between brain and speech, it is the merit of the century of enlightenment to have examined the problem of these relationships. To accept the fact that language was a product of the physical nature of humans, it was necessary to demonstrate that language abilities could originate from our activities and not from a gift of God and to explain that language was in fact the product of human social life. This article shows the most significant steps of these efforts by the thinkers of the eighteenth century to reevaluate in a more realistic way the whole problem of language's origin and of the physical conditions that determine the acquisition of speech by humankind. Meanwhile, new theories about the brain and the nervous system give some support to those who definitely wish to see language merely as a human product.

[Cervical adenopathies in relation to AIDS. Course of histological aspects. Diagnostic and prognostic value]. / Les adénopathies cervicales en relation avec le SIDA. Evolution des aspects histologiques. Valeur diagnostique et pronostique.

Histopathologic appearances of lymph nodes during acquired immune deficiency syndrome (AIDS) and related conditions are analyzed, with emphasis on the diagnostic and prognostic value of cervical gland biopsy at the lymphadenopathic stage. Details are given of the characteristics of the follicular hyperplasia of the lymph nodes (type I), which appears to be the initial lesion and is possibly regressive, and emphasis placed on the poor prognostic significance of the hyperplasia simulating a Castleman syndrome and of the forms simulating an angioimmunoblastic lymphadenopathy (type II). Findings suggest that the appearance, in a still hyperplastic lymph nodes, of foci of pseudo-angioimmunoblastic homogenization, of fibroedema with lymphoid depletion or conjunctival vascular proliferation may be the initial sign of a course towards the glandular atrophy (type III) or Kaposi's sarcoma which are the attribute of confirmed AIDS.

Contraception and screening for cervical and breast cancer in neuromuscular disease: a retrospective study of 50 patients monitored at a clinical reference centre.

OBJECTIVE: To analyse contraceptive methods and the extent of screening for breast and cervical cancer in women with neuromuscular disease, compare these results with data and guidelines for the general population and determine the environmental and attitudinal barriers encountered. PATIENTS AND METHODS: A retrospective, descriptive study in a population of female neuromuscular disease patients (aged 20 to 74) monitored at a clinical reference centre. RESULTS: Complete datasets were available for 49 patients. Seventy percent used contraception (hormonal contraception in most cases). Sixty-eight percent had undergone screening for cervical cancer at some time in the previous 3 years and 100% of the patients over 50 had undergone a mammography. Architectural accessibility and practical problems were the most common barriers to care and were more frequently encountered by wheelchair-bound, ventilated patients. CONCLUSIONS: In general, the patients had good access to contraceptive care and cervical and breast cancer screening. However, specific measures may be useful for the most severely disabled patients.

Management of low back pain in primary care prior to multidisciplinary functional restoration: a retrospective study of 72 patients.

OBJECTIVE: Chronic low back pain is a major socioeconomic health issue, due to the high direct (healthcare) and indirect (sick leave) costs. The aim of the present study was to describe the primary care management of low back pain patients prior to their inclusion in a multidisciplinary functional restoration network. METHODS: A descriptive, retrospective, questionnaire-based survey of the general practitioners dealing with 72 low back pain patients. RESULTS: Patients had been monitored by their general practitioner for an average of four years, with a mean frequency of eight appointments per year per patient. Ninety-three percent and 60% of the patients had been referred to a rheumatologist and a surgeon, respectively. Ninety-eight percent had had lumbar radiographies, 80% had undergone a computed tomography scan and 64% had undergone magnetic resonance imaging. The most commonly prescribed medications were anti-inflammatories and first- or second-line analgesics. Thirty percent had already received morphine analgesics and 50% had taken antidepressants. Thirty-two percent had undergone lumbar surgery. Physiotherapy was frequently reported and, indeed, 6% of patients had participated in over 100 sessions. Total sick leave averaged 8.25 months over the study's follow-up period. CONCLUSION: The time interval before referral to a multidisciplinary care team is long and so GPs should be encouraged and helped to organize this process earlier. It is also essential to determine factors which predict progression to chronic LBP.

Nitrosative and oxidative modulation of iron regulatory proteins.

Cytokine-driven nitric oxide (NO) synthase II provides cells with effectors for reactions at redox-sensitive site(s) of proteins. Iron regulatory proteins (IRP1 and IRP2), two post-transcriptional regulators of gene expression, are particularly sensitive to NO synthesis and to oxidative stress. IRP1 possesses a redox-active Fe-S cluster and can also exhibit aconitase activity. IRP2 has no Fe-S cluster but exhibits several redox-sensitive cysteine residues. Under proper redox conditions, both IRPs bind to iron-responsive elements in the untranslated region of mRNAs encoding proteins involved in iron metabolism and energy production. This review describes and compares the effects of NO, peroxynitrite, and reactive oxygen species on these two chemosensitive proteins.

Nitric oxide-inducible expression of heme oxygenase-1 in human cells. Translation-independent stabilization of the mRNA and evidence for direct action of nitric oxide.

Expression of heme oxygenase-1 (HO-1) in mammalian cells contributes to resistance to various types of free radical damage. Nitric oxide (NO) induces HO-1 in many cell types, but the specific contribution of transcriptional or post-transcriptional effects to this induction have remained unresolved. Here we show that the extent of HO-1 mRNA expression in IMR-90 and HeLa cells depends on the rate of NO delivery, and that the induction occurs more slowly in HeLa than in human fibroblast (IMR-90) cells. We used a specific NO scavenger (2-(4-carboxylphenyl)-4,4,5,5-tetramethylimidazolin-1-oxyl 3-oxide) that completely prevented the inducible expression of HO-1 by NO, pointing to direct signaling action of NO in this induction. By inhibiting transcription during the NO exposure, we have confirmed that NO treatment activates a mechanism that stabilizes HO-1 mRNA. The increase in the HO-1 mRNA half-life in IMR-90 cells was directly correlated with increasing rates of NO release. We also show here that the stabilization of the HO-1 message does not require de novo protein synthesis. Collectively, these results show that stabilization of HO-1 mRNA can be finely tuned to the NO exposure, and that the effect in human fibroblasts is mediated by a pre-existing protein.

DRAGON: Database Referencing of Array Genes Online.

UNLABELLED: "Database Referencing of Array Genes ONline" or "DRAGON" is a web-accessible database that aids in the analysis of differential gene expression data as a biological annotation tool. Users of DRAGON can submit data sets containing large lists of genes and then choose particular characteristics that DRAGON supplies for all genes on the list rapidly and simultaneously. AVAILABILITY: The DRAGON database is available for queries on the DRAGON web site www.kennedykrieger.org/pevsnerlab/dragon.htm. CONTACT: pevsner@kennedykrieger.org or cbouton@jhmi.edu

[Appearance of the uterine mucosa in the puberal female rat after continuous exposure to light or early androgenization]. / Aspect de la muqueuse utérine de ratte pubère après illumination continue ou androgénisation précoce

Female Albino rats exposed to permanent light or androgenized at birth exhibit structural modifications of the uterine mucosa similar to the women's affected by the stein Leventhal syndrome.

Modulation by nitric oxide of metalloprotein regulatory activities.

In many cells, a nitric oxide (NO) synthase inducible by immunological stimuli produces a sustained flow of NO that lasts a long time. NO is a short-lived molecule but it is a diffusible ligand believed to be capable of reaching distal target sites. Further, several lines of evidence indicate that cysteine-rich motifs of metal-binding proteins, as well as redox-sensitive metal clusters of metalloproteins, are natural sensors of bioradicals like NO. In metalloregulatory proteins, metals are often conveniently located at binding sites and bound to cysteine residues. Accordingly, disruption of the metal-thiolate polymetallic clusters should trigger significant remodelling of the protein structure involved in regulation. We can therefore postulate that the nitrosation reaction occurring at metal centres or cysteine-rich motifs will preclude correct binding to regulatory sites. Several examples are given of metalloregulatory proteins whose metal is bound to thiols and may then become sensitive to NO. Recent observations indicate that in response to NO synthesis, iron regulatory protein, a eukaryotic bifunctional [Fe-S] protein, switches from acting as aconitase to being an RNA-binding regulator, and we suggest that the interplay between NO or a NO-derived molecule and metal clusters at critical allosteric sites may be a crucial component of the cellular response to environmental stress.