Minimally conscious state plus versus minus: Likelihood of emergence and long-term functional independence.

OBJECTIVE: Severe brain injuries can result in disorders of consciousness, such as the Minimally Conscious State (MCS), where individuals display intermittent yet discernible signs of conscious awareness. The varied levels of responsiveness and awareness observed in this state have spurred the progressive delineation of two subgroups within MCS, termed "plus" (MCS+) and "minus" (MCS-). However, the clinical validity of these classifications remains uncertain. This study aimed to investigate and compare the likelihood of emergence from MCS, as well as the functional independence after emergence, in individuals categorized as in MCS+ and MCS-. METHODS: Demographic and behavioral data of 80 participants, admitted as either in MCS+ (n = 30) or MCS- (n = 50) to a long-term neurorehabilitation unit, were retrospectively analyzed. The neurobehavioral condition of each participant was evaluated weekly until discharge, demise, or emergence from MCS. The functional independence of those participants who emerged from MCS was assessed 6 months after emergence. RESULTS: While only about half of the individuals classified as in MCS- (n = 24) emerged from the MCS, all those admitted as in MCS+ did, and in a shorter postinjury period. Despite these differences, all individuals who emerged from the MCS demonstrated similar high disability and low functional independence 6 months after emergence, regardless of their state at admission. INTERPRETATION: Individuals classified as MCS+ exhibited a higher likelihood of emergence and a shorter time to emergence compared to those in MCS-. However, the level of functional independence 6 months after emergence was found to be unrelated to the initial state at admission.

Behavioral signs of recovery from unresponsive wakefulness syndrome to emergence of minimally conscious state after severe brain injury.

Precise description of behavioral signs denoting transition from unresponsive wakefulness syndrome/vegetative state (UWS/VS) to minimally conscious state (MCS) or emergence from MCS after severe brain injury is crucial for prognostic purposes. A few studies have attempted this goal but involved either non-standardized instruments, limited temporal accuracy or samples, or focused on (sub)acute patients. The objective of this study was to describe the behavioral signs that led to a change of diagnosis, as well as the factors influencing this transition, in a large sample of patients with chronic disorders of consciousness after severe brain injury. In this retrospective cohort study, 185 patients in UWS/VS or MCS were assessed with the Coma Recovery Scale Revised (CRS-R) five times within the two weeks following their admission to a neurorehabilitation center and then weekly until emergence from MCS, discharge or death. Of these 185 patients, 33 patients in UWS/VS and 45 patients in MCS transitioned to another state. Transition to MCS was mostly denoted by one behavioral sign (72%), predominantly visual fixation (57%), followed by localization to noxious stimulation (27%), visual pursuit (21%) and object manipulation (12%), and could be predicted by etiology, time post-injury and age. Emergence from MCS was characterized by one sign in 64% of patients and by two signs (functional communication and objects use) in the remaining cases, and could be predicted by time post-injury and number of behavioral signs at admission. Clinicians should be therefore advised to pay particular attention to visual and motor subscales of the CRS-R to detect behavioral recovery.

When, How, and to What Extent Are Individuals with Unresponsive Wakefulness Syndrome Able to Progress? Neurobehavioral Progress.

Accurate estimation of the neurobehavioral progress of patients with unresponsive wakefulness syndrome (UWS) is essential to anticipate their most likely clinical course and guide clinical decision making. Although different studies have described this progress and possible predictors of neurobehavioral improvement in these patients, they have methodological limitations that could restrict the validity and generalization of the results. This study investigates the neurobehavioral progress of 100 patients with UWS consecutively admitted to a neurorehabilitation center using systematic weekly assessments based on standardized measures, and the prognostic factors of changes in their neurobehavioral condition. Our results showed that, during the analyzed period, 34% of the patients were able to progress from UWS to minimally conscious state (MCS), 12% of the total sample (near one third from those who progressed to MCS) were able to emerge from MCS, and 10% of the patients died. Transition to MCS was mostly denoted by visual signs, which appeared either alone or in combination with motor signs, and was predicted by etiology and the score on the Coma Recovery Scale-Revised at admission with an accuracy of 75%. Emergence from MCS was denoted in the same proportion by functional communication and object use. Predictive models of emergence from MCS and mortality were not valid and the identified predictors could not be accounted for.

When, How, and to What Extent Are Individuals with Unresponsive Wakefulness Syndrome Able to Progress? Functional Independence.

Accurate estimation of the functional independence of patients with unresponsive wakefulness syndrome (UWS) is essential to adjust family and clinical expectations and plan long-term necessary resources. Although different studies have described the clinical course of these patients, they have methodological limitations that could restrict generalization of the results. This study investigates the neurobehavioral progress of 100 patients with UWS consecutively admitted to a neurorehabilitation center using systematic weekly assessments based on standardized measures, and the functional independence staging of those patients who emerged from a minimally conscious state (MCS) during the first year post-emergence. Our results showed that one year after emergence, most patients were severely dependent, although some of them showed extreme or moderate severity. Clinically meaningful functional improvement was less likely to occur in cognitively-demanding activities, such as activities of daily living and executive function. Consequently, the use of specific and staging functional independence measures, with domain-specific evaluations, are recommended to detect the functional changes that might be expected in these patients. The information provided by these instruments, together with that obtained from repeated assessments of the preserved consciousness with standardized instruments, could help clinicians to adjust expectations and plan necessary resources for this population.

FS222, a CD137/PD-L1 Tetravalent Bispecific Antibody, Exhibits Low Toxicity and Antitumor Activity in Colorectal Cancer Models.

PURPOSE: With the increased prevalence in checkpoint therapy resistance, there remains a significant unmet need for additional therapies for patients with relapsing or refractory cancer. We have developed FS222, a bispecific tetravalent antibody targeting CD137 and PD-L1, to induce T-cell activation to eradicate tumors without the current toxicity and efficacy limitations seen in the clinic. EXPERIMENTAL DESIGN: A bispecific antibody (FS222) was developed by engineering CD137 antigen-binding sites into the Fc region of a PD-L1 IgG1 mAb. T-cell activation by FS222 was investigated using multiple in vitro assays. The antitumor efficacy, survival benefit, pharmacodynamics, and liver pharmacology of a murine surrogate molecule were assessed in syngeneic mouse tumor models. Toxicology and the pharmacokinetic/pharmacodynamic profile of FS222 were investigated in a non-human primate dose-range finding study. RESULTS: We demonstrated simultaneous binding of CD137 and PD-L1 and showed potent T-cell activation across CD8+ T-cell activation assays in a PD-L1-dependent manner with a CD137/PD-L1 bispecific antibody, FS222. FS222 also activated T cells in a human primary mixed lymphocyte reaction assay, with greater potency than the monospecific mAb combination. FS222 showed no signs of liver toxicity up to 30 mg/kg in a non-human primate dose-range finding study. A surrogate molecule caused significant tumor growth inhibition and survival benefit, concomitant with CD8+ T-cell activation, in CT26 and MC38 syngeneic mouse tumor models. CONCLUSIONS: By targeting CD137 agonism to areas of PD-L1 expression, predominantly found in the tumor microenvironment, FS222 has the potential to leverage a focused, potent, and safe immune response augmenting the PD-(L)1 axis blockade.

Behavioral recovery in disorders of consciousness: a prospective study with the Spanish version of the Coma Recovery Scale-Revised.

OBJECTIVE: To describe the clinical characteristics and short-term pattern of evolution of a sample of patients within 1 year after acquiring a brain injury that led to a vegetative state (VS) or a minimally conscious state (MCS). DESIGN: Cohort study. SETTING: Inpatient brain injury rehabilitation program. PARTICIPANTS: Patients with acquired brain injury (N=32; 47% traumatic, 37.5% hemorrhagic, 15.5% anoxic) who were in a VS or an MCS according to Coma Recovery Scale-Revised (CRS-R) scores. INTERVENTION: Integrative multisensory program comprising daily physical rehabilitation procedures and multimodal sensory stimulation. MAIN OUTCOME MEASURE: All patients were assessed with a Spanish version of the CRS-R at admission and then monthly for at least 6 months or until emergence from MCS. RESULTS: At the time of admission, 12 patients were diagnosed as being in a VS and 20 as being in an MCS. Eight patients were able to emerge from their MCS during follow-up. Seven of these 8 patients were diagnosed as being in an MCS at inclusion, and only 1 was diagnosed as being in a VS. Emergence from an MCS was mostly associated with improvement in both the communication and motor function scales (n=4). Lesser chronicity (P=.01) and the presence of more than visual behavioral responses at admission (P=.05) were both significant predictors of emergence from an MCS. CONCLUSIONS: The CRS-R seems appropriate for establishing an immediate prognosis in this population. A quick referral of these patients for specialized assessment and rehabilitation facilities is recommended.

Dihydroceramide desaturase and dihydrosphingolipids: debutant players in the sphingolipid arena.

Sphingolipids are a wide family of lipids that share common sphingoid backbones, including (2S,3R)-2-amino-4-octadecane-1,3-diol (dihydrosphingosine) and (2S,3R,4E)-2-amino-4-octadecene-1,3-diol (sphingosine). The metabolism and biological functions of sphingolipids derived from sphingosine have been the subject of many reviews. In contrast, dihydrosphingolipids have received poor attention, mainly due to their supposed lack of biological activity. However, the reported biological effects of active site directed dihydroceramide desaturase inhibitors and the involvement of dihydrosphingolipids in the response of cells to known therapeutic agents support that dihydrosphingolipids are not inert but are in fact biologically active and underscore the importance of elucidating further the metabolic pathways and cell signaling networks involved in the biological activities of dihydrosphingolipids. Dihydroceramide desaturase is the enzyme involved in the conversion of dihydroceramide into ceramide and it is crucial in the regulation of the balance between sphingolipids and dihydrosphingolipids. Furthermore, given the enzyme requirement for O2 and the NAD(P)H cofactor, the cellular redox balance and dihydroceramide desaturase activity may reciprocally influence each other. In this review both dihydroceramide desaturase and the biological functions of dihydrosphingolipids are addressed and perspectives on this field are discussed.

Dihydrosphingomyelin impairs HIV-1 infection by rigidifying liquid-ordered membrane domains.

The lateral organization of lipids in cell membranes is thought to regulate numerous cell processes. Most studies focus on the coexistence of two fluid phases, the liquid crystalline (l(d)) and the liquid-ordered (l(o)); the putative presence of gel domains (s(o)) is not usually taken into account. We show that in phospholipid:sphingolipid:cholesterol mixtures, in which sphingomyelin (SM) promoted fluid l(o) domains, dihydrosphingomyelin (DHSM) tended to form rigid domains. Genetic and pharmacological blockade of the dihydroceramide desaturase (Des1), which replaced SM with DHSM in cultured cells, inhibited cell infection by replication-competent and -deficient HIV-1. Increased DHSM levels gave rise to more rigid membranes, resistant to the insertion of the gp41 fusion peptide, thus inhibiting viral-cell membrane fusion. These results clarify the function of dihydrosphingolipids in biological membranes and identify Des1 as a potential target in HIV-1 infection.

Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells.

Resveratrol has both apoptosis and autophagy-promoting activities in different cancer cells. Dihydroceramide is the immediate precursor of the apoptotic mediator ceramide in the de novo sphingolipid synthesis pathway. Here we demonstrate that resveratrol induces autophagy in HGC-27 cells, with no sign of cell death. Autophagy occurs after an increase in dihydroceramides by inhibition of dihydroceramide desaturase. The effects of resveratrol are mimicked by a dihydroceramide desaturase inhibitor. These results demonstrate that resveratrol-induced autophagy occurs with a rise in intracellular dihydroceramide levels as the result of inhibition of dihydroceramide desaturases activity and that dihydroceramide accumulation is responsible for autophagy promotion.

Synthesis and biological activity of a novel inhibitor of dihydroceramide desaturase.

A novel mechanism-based dihydroceramide desaturase inhibitor (XM462) in which the substrate C5 methylene group is replaced by a sulfur atom is reported. Dihydroceramide desaturase inhibition occurred both in vitro and in cultured cells with IC(50) values of 8.2 and 0.78 microM, respectively, at a substrate concentration of 10 microM. In vitro experiments showed that XM462 produced a mixed-type inhibition (K(i)=2 microM, alpha=0.83). LC-MS analyses showed that accumulation of endogenous dihydroceramides occurred in cells upon treatment with XM462 in serum-free medium, whereas ceramides built up in controls. In addition, XM462 was found to be metabolised to its 1-glucosyl and 1-phosphocholine derivatives, and to the products of N-deacylation and reacylation with palmitoyl and stearoyl groups. In Jurkat A3 cells cultured in serum-free medium, viability, as the percentage of trypan blue unstained cells in total cells, was reduced upon XM462 treatment (5 microM, 24 h), but not in controls. The interest of this compound is discussed.

Co-expression of the mosquitocidal toxins Cyt1Aa and Cry11Aa from Bacillus thuringiensis subsp. israelensis in Asticcacaulis excentricus.

The cyt1Aa gene from Bacillus thuringiensis subsp. israelensis (Bti), whose product synergizes other mosquitocidal toxins, and functions as a repressor of resistance developed by mosquitoes against Bacilli insecticides, was introduced into the aquatic Gram-negative bacterium Asticcacaulis excentricus alongside the cry11Aa gene. The genes were introduced as an operon, but although mRNA was detected for both genes, no Cyt1Aa toxin was detected. Both proteins were expressed using a construct in which a promoter was inserted upstream of each gene. Recombinant A. excentricus expressing both toxins was found to be approximately twice as toxic to third instar larvae of Culex quinquefasciatus as transformants expressing just Cry11Aa.

Reconstrucción de brazo afectado por tumor de células de Merkel, con colgajo gran dorsal pediculado / Latissimus dorsi pedicled flap in arm reconstruction after Merkel cell carcinoma resection

Latissimus dorsi flap is versatile to cover local defects as at distance. The tumor of cells of Merkel is not very frequent and it appears in exposed areas in the sun. Case Report: Patient female 55 years with tumoracion in left arm. Tumoracion is dried up and it is carried out reconstruction of the area with a ipsilateral. Latissimus dorsi flap. Conclusion: The tumor of Merkel involves an extensive area of the left arm, creating a great defect in the resection. Latissimus dorsi flap contributes muscular and cutaneous to cover the great and deep defects. for the reconstruction.