Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Muscle coactivation during gait in children with and without cerebral palsy.

BACKGROUND: Children with Cerebral Palsy (CP) walk with an uncoordinated gait compared to Typically Developing (TD) children. This behavior may reflect greater muscle co-activation in the lower limb; however, findings are inconsistent, and the determinants of this construct are unclear. RESEARCH OBJECTIVES: (i) Compare lower-limb muscle co-activation during gait in children with, and without CP, and (ii) determine the extent to which muscle co-activation is influenced by electromyography normalization procedures and Gross Motor Function Classification System (GMFCS) class. METHODS: An electromyography system measured muscle activity in the rectus femoris, semitendinosus, gastrocnemius, and tibialis anterior muscles during walking in 46 children (19 CP, 27 TD). Muscle co-activation was calculated for the tibialis anterior-gastrocnemius (TA-G), rectus femoris-gastrocnemius (RF-G), and rectus femoris-semitendinosus (RF-S) pairings, both using root mean squared (RMS)-averaged and dynamically normalized data, during stance and swing. Mann-Whitney U and independent t-tests examined differences in muscle co-activation by group (CP vs. TD) and GMFCS class (CP only), while mean difference 95% bootstrapped confidence intervals compared electromyography normalization procedures. RESULTS: Using dynamically normalized data, the CP group had greater muscle co-activation for the TA-G and RF-G pairs during stance (p < 0.01). Using RMS-averaged data, the CP group had greater muscle co-activation for TA-G (stance and swing, p < 0.01), RF-G (stance, p < 0.05), and RF-S (swing, p < 0.01) pairings. Muscle co-activation calculated with dynamically normalized, compared to RMS-averaged data, were larger in the RF-S and RF-G (stance) pairs, but smaller during swing (RF-G). Children with CP classified as GMFCS II had greater muscle co-activation during stance in the TA-G pair (p < 0.05). SIGNIFICANCE: Greater muscle co-activation observed in children with CP during stance may reflect a less robust gait strategy. Although data normalization procedures influence muscle co-activation ratios, this behavior was observed independent of normalization technique.

Declining levels of serum chemokine (C-X-C motif) ligand 10 over time are associated with new onset of psoriatic arthritis in patients with psoriasis: a new biomarker?

BACKGROUND: We previously found that serum levels of chemokine (C-X-C motif) ligand 10 (CXCL10) decreased after the onset of psoriatic arthritis (PsA). OBJECTIVES: We measured CXCL10 levels over time in patients with psoriasis who developed PsA to determine whether the drop in CXCL10 was specific to these patients and further assess its association with PsA development. METHODS: Prospectively followed patients with psoriasis without arthritis [cutaneous psoriasis (PsC)] were assessed yearly by rheumatologists for the presence of PsA. Patients with PsC who developed PsA (converters) were matched to those that did not develop PsA (nonconverters) based on psoriasis duration and the interval between follow-up visits. The duration between baseline and the first visit postconversion in converters was used to assign a pseudoconversion date in nonconverters. Linear mixed-effects models were used to model the expression of CXCL10 over time. RESULTS: CXCL10 significantly declined over time in converters prior to PsA development with a significant difference in the trend over time between converters (n = 29) and nonconverters (n = 52; P < 0·001). CXCL10 continued to decline after PsA onset in a subset of converters. There was a significant difference in the trend of CXCL10 levels between converters (n = 24) and nonconverters (n = 16; P = 0·01) preconversion/pseudoconversion. This difference remained postconversion (P = 0·006) and was not different from the preconversion period (P = 0·75). CONCLUSIONS: A large difference in CXCL10 was identified in patients with PsC that are destined to develop PsA over time. This exploratory analysis supports the association of CXCL10 with PsA development in patients with PsC and warrants further study of the predictive ability of this chemokine. What is already known about this topic? Chemokine (C-X-C motif) ligand 10 (CXCL10) is elevated in psoriatic affected tissues and serum and/or plasma. Patients with psoriasis that develop psoriatic arthritis (PsA) have elevated CXCL10 levels at baseline and these levels drop after arthritis onset. What does this study add? By monitoring levels of CXCL10 in serum over multiple visits in patients with psoriasis that develop PsA as well as those that do not develop PsA, an association was identified between CXCL10 and PsA development. What is the translational message? CXCL10 is a strong candidate for use by physicians for the detection of patients with psoriasis that are at risk of developing PsA. Linked Comment: Kirby and Fitzgerald. Br J Dermatol 2020; 183:805-806.

Dietary encapsulated probiotic effect on broiler serum biochemical parameters.

AIM: The study aimed to evaluate the effect of encapsulated probiotic bacteria (Lactobacillus lactis and Bifidobacterium bifidum) on broiler serum biochemical parameters. MATERIALS AND METHODS: Encapsulation protects the probiotics and increases their livability on exposure to unfavorable processing and storage temperatures and gastrointestinal pH. Hence, an in vitro study was undertaken to encapsulate the probiotic bacteria L. lactis and B. bifidum with sodium alginate and chitosan and evaluate the encapsulation efficiency. This experiment was conducted with 288-day-old broiler chicken; they were distributed randomly into eight treatments and six replicates in each treatment (six birds in each replicate) and given with standard feed. RESULTS: Supplementation of the encapsulated bacteria either alone or in combination (T4, T6, and T8) significantly (p<0.05) increased mean total serum protein, albumin, and globulin as compared to the birds that were not supplemented with any probiotic (T1 and T2) or supplemented with non-encapsulated bacteria (T3, T5, and T7). Supplementation of the encapsulated bacteria either alone or in combination (T4, T6, and T8) significantly (p<0.05) lowered mean total serum cholesterol, serum low-density lipoprotein (LDL) cholesterol, and serum triglycerides, as compared to the birds that were not supplemented with any probiotic (T1 and T2) or supplemented with non-encapsulated bacteria (T3, T5, and T7). CONCLUSION: It may be concluded that supplementation of the encapsulated probiotic bacteria either alone or in combination significantly increased total serum protein, albumin, and globulin and significantly lowered mean total serum cholesterol, serum LDL cholesterol, and serum triglycerides as compared to the birds that were not supplemented with any probiotic or supplemented with non-encapsulated bacteria.

Arachnoid Cyst Causing Depression and Neuropsychiatric Symptoms: a Case Report.

Arachnoid cysts are benign space-occupying brain lesions that contain cerebrospinal fluid. Most cases are congenital in origin, caused by failed fusion of the arachnoid membrane early in fetal development. Cases are often incidentally detected on neuroimaging; however, rarely patients present with neuropsychiatric manifestations when cysts expand and cause a midline shift, compression of nearby brain tissue or cerebrospinal fluid compartments or both. We report a case of a 56-year-old woman with no past history or family history of psychiatric illness who developed acute-onset right-sided weakness, depressive symptoms, and other neuropsychiatric deficits. A diagnosis of organic mood disorder caused by an arachnoid cyst was made. Her symptoms and neuropsychiatric deficits remitted after cyst marsupialisation by open craniotomy. Therefore, it is important to investigate the organic aetiology in elderly patients who present with simultaneous mood disorder and cognitive dysfunction.

Systemic inflammation and painful joint burden in osteoarthritis: a matter of sex?

OBJECTIVE: We investigated the association between serum levels of C-reactive protein (CRP) and the extent of multijoint pain among individuals with hip/knee osteoarthritis (OA) and determined whether the association differs by sex. DESIGN: Serum CRP and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay (ELISA) in 189 individuals (101 female, 88 male) scheduled for total hip/knee arthroplasty for OA. Patients indicated on a homunculus all painful joints; a summed count was derived. A series of negative binomial regression models was used to investigate the cross-sectional association between painful joint count (outcome) and serum CRP concentrations, adjusting for age, sex, body mass index (BMI), comorbidity count and COMP. An interaction between sex and these biomarkers was tested. RESULTS: Mean age: 66 among women, 65 among men. Women had higher mean joint count (3.7 vs 2.5, P < 0.01; 4+ joint count reported by 37% women, 25% men). Median CRP concentration was higher in women (15.4 mg/l vs 9.3, P = 0.07). From adjusted analyses, the effects of both ln(CRP) and ln(COMP) were modified by sex (P < 0.05). Increasing ln(CRP) was associated with greater painful joint count among women, but not men. CONCLUSIONS: There may be a dose-response association between painful joint burden in OA and systemic inflammation, and it appears the association is sex-specific, which may in part explain inconsistent findings in the literature. Our results underline the importance of showing sex-specific associations in OA, especially when studying the influence of inflammation.

Mechanical properties, biological behaviour and drug release capability of nano TiO2-HAp-Alginate composite scaffolds for potential application as bone implant material.

Nanocomposite scaffolds of TiO2 and hydroxyapatite nanoparticles with alginate as the binding agent were fabricated using the freeze drying technique. TiO2, hydroxyapatite and alginate were used in the ratio of 1:1:4. The scaffolds were characterized using X-ray diffraction, fourier transform infrared spectroscopy, and scanning electron microscopy. The biocompatibility of the scaffolds was evaluated using cell adhesion and MTT assay on osteosarcoma (MG-63) cells. Scanning electron microscopy analysis revealed that cells adhered to the surface of the scaffolds with good spreading. The mechanical properties of the scaffolds were investigated using dynamic mechanical analysis. The swelling ability, porosity, in vitro degradation, and biomineralization of the scaffolds were also evaluated. The results indicated controlled swelling, limited degradation, and enhanced biomineralization. Further, drug delivery studies of the scaffolds using the chemotherapeutic drug methotrexate exhibited an ideal drug release profile. These scaffolds are proposed as potential candidates for bone tissue engineering and drug delivery applications.

Enhanced Activity of Topical Hydrocortisone by Competitive Binding of Corticosteroid-Binding Globulin.

Atopic dermatitis of sensitive areas such as the face, particularly in children, is a difficult disease to treat as the standard therapeutic, topical steroids, is contraindicated for this application in children. Hydrocortisone (HC) can be used in these instances because it has been shown to be safe, but is often ineffective as it is a relatively weak steroid, especially at over-the-counter concentrations. To enhance the local topical activity of HC, the terminal inactive metabolite of prednisolone, Δ(1)-cortienic acid (Δ(1)-CA), is added to HC, as Δ(1)-CA preferentially binds transcortin, liberating more HC to elicit its therapeutic effect. Skin blanching studies, which are used to evaluate the potency of topical steroids, were employed to assess the ability of Δ(1)-CA to enhance the activity of HC. The results demonstrate that Δ(1)-CA, when applied in combination with HC, does indeed potentiate the vasoconstriction effect of topically applied HC, while having no effect alone. Thus, addition of the inert prednisolone metabolite Δ(1)-CA can increase the therapeutic effect of over-the-counter concentrations of HC when applied topically.

Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells.

Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. The identification of cancer cell internalizing antigens for drug targeting to the hypoxic tumour niche remains a challenge of high clinical relevance. Here we show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. We find that hypoxic down-regulation of constitutive endocytosis is HIF-independent, and involves caveolin-1-mediated inhibition of dynamin-dependent, membrane raft endocytosis. Caveolin-1 overexpression inhibits protein internalization, suggesting a general negative regulatory role of caveolin-1 in endocytosis. In contrast to this global inhibitory effect, we identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia. We demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. Our data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumour microenvironment.

Accuracy of the composite variability index as a measure of the balance between nociception and antinociception during anesthesia.

BACKGROUND: The Composite Variability Index (CVI), derived from the electroencephalogram, was developed to assess the antinociception-nociception balance, whereas the Bispectral Index (BIS) was developed to assess the hypnotic state during anesthesia. We studied the relationships between these indices, level of hypnosis (BIS level), and antinociception (predicted remifentanil effect-site concentrations, CeREMI) before and after stimulation. Also, we measured their association with movement in response to a noxious stimulus. METHODS: We randomized 120 patients to one of 12 groups targeting different hypnotic levels (BIS 70, 50, and 30) and various CeREMI (0, 2, 4, or 6 ng/mL). At pseudo-steady state, baseline values were observed, and a series of stimuli were applied. Changes in BIS, CVI, heart rate (HR), and mean arterial blood pressure (MAP) between baseline and response period were analyzed in relation to level of hypnosis, antinociception, and somatic response to the stimuli. RESULTS: CVI and BIS more accurately correlate with somatic response to an Observer Assessment of Alertness and Sedation-noxious stimulation than HR, MAP, CeREMI, and propofol effect-site concentration (Tukey post hoc tests P < 0.01). Change in CVI is more adequate to monitor response to stimulation than changes in BIS, HR, or MAP (as described by the Mathews Correlation Coefficient with significance level set at P < 0.001). In contrast, none of the candidate analgesic state indices was uniquely related to a specific opioid concentration and is extensively influenced by the hypnotic state as measured by BIS. CONCLUSIONS: CVI appears to correlate with somatic responses to noxious stimuli. However, unstimulated CVI depends more on hypnotic drug effect than on opioid concentration.

Radiological characteristics of the calcaneal spurs in psoriatic arthritis.

OBJECTIVES: Inflammation at the entheses is a distinguishing feature of psoriatic arthritis (PsA). Enthesitis at the heel is the most common location at the Achilles and plantar fascia insertions on the calcaneus. This study aimed to 1) describe the morphological features and measurements of plantar calcaneal spurs in subjects with PsA and controls and 2) determine radiological features that differentiate between inflammatory and non-inflammatory calcaneal spurs. METHODS: Weight bearing lateral foot radiographs of 101 subjects with PsA and 38 control subjects without inflammatory arthritis were examined for plantar calcaneal and Achilles spurs. Three measurements were taken from each radiograph: plantar spur base, mid-segment, and length in millimeters. The differences in radiographic measurements, and the presence of fluffy periostitis of the plantar spurs were then compared between PsA patients and controls. RESULTS: Of the 101 subjects with PsA, 76 (75%) had at least one plantar calcaneal spur and 32 (31.5%) had at least one Achilles tendon spur, compared to 18 (47%) and 3 (8%) respectively in control group (p=0.004). Fluffy plantar periostitis was identified in 14 PsA subjects and none of the controls (p=0.01). The dimensions of plantar spurs were significantly different between groups - longer mid-segment distinguished patients with PsA from controls. CONCLUSIONS: Calcaneal spurs are more common in subjects with PsA than controls. Longer mid-segment measurement was associated with PsA. This study indicates that the presence of fluffy plantar periostitis and broad based and longer mid-segment dimensions are radiological features for inflammatory spurs.

Prevalence and predictors of reduced work productivity in patients with psoriatic arthritis.

OBJECTIVES: Psoriatic arthritis (PsA) is a unique inflammatory musculoskeletal disorder associated with psoriasis. Although high rates of absenteeism have been associated with PsA, less is known about the impact of the disease on the productivity of patients who remain at work. The aim of this study was to identify factors associated with reduced work productivity, as measured by the Work Limitations Questionnaire (WLQ), among patients with PsA. METHODS: Patients attending a single Psoriatic Arthritis Clinic were recruited for participation. Employed participants (including homemakers) first completed a Questionnaire for the Assessment of Work-Related Factors (QAWRF). Eligible participants then completed the WLQ. WLQ scores were used as the dependent variable in linear and logistic regression analyses. Independent variables assessed in this study include work characteristics, demographic factors, and clinical measures. RESULTS: One hundred and eighty-six eligible patients (60.9% males) returned their assessment forms for analysis. The mean reduction in work productivity due to illness was 4.3%. In univariate linear regression analysis, work productivity was significantly associated with sex, education status, Psoriasis Area and Severity Index (PASI), AJC, ESR, Functional Co-morbidity Index (FCI), and support at work; associations with gender, ESR, FCI, and medications were also significant in a reduced multivariate model. CONCLUSIONS: Work productivity was associated with demographic, clinical, and work-related factors in PsA. These variables may be useful in identifying patients who require more aggressive intervention, including the use of effective drugs to control disease activity and advocacy for a more supportive work environment.

Lupus - the cold, hard facts.

Systemic lupus erythematosus (SLE) is a multisystem chronic disease with a multitude of clinical presentations. We review and synthesize how an environmental insult (exposure to extreme cold for a short duration) and endogenous (antiphospholipid antibody syndrome, SLE vasculitis) insults in a susceptible young female with lupus (peripheral arterial disease, smoking, SLE) led to a perfect storm resulting in catastrophic injuries (frostbite).

The functional MICA-129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA-B and HLA-C.

A methionine/valine polymorphism at amino acid 129 of the major histocompatibility complex class I chain-related gene A (MICA-129) categorizes alleles into strong and weak binders of the natural killer (NK) and T-cell receptor NKG2D. We investigated whether MICA-129 is differentially associated with skin and joint manifestations of psoriatic disease (PsD) independently of human leukocyte antigen (HLA)-C and HLA-B in patients and controls from Toronto and St. John's. The MICA-129 methionine (Met) allele, particularly Met/Met homozygosity, was strongly associated with both cutaneous psoriasis (PsC) and psoriatic arthritis (PsA) independently of HLA-B and HLA-C in Toronto patients, and was also associated with PsA in St. John's patients, but with no additional effect of Met/Met homozygosity. No association remained after adjustment for HLA alleles in St. John's patients. MICA-129 was not associated with PsA when compared with PsC. We conclude that MICA-129 is a marker of skin manifestations of PsD that is independent of HLA class I in Toronto patients.

Closure of bronchopleural fistula by interventional bronchoscopy using sealants and endobronchial devices.

BACKGROUND: Bronchopleural fistula (BPF) is a communication in the form of a sinus tract between the pleural space and the bronchial tree. Chronic bronchopleural fistula (BPF) is a rare but a serious complication of several pulmonary and postoperative conditions. BPF carries a high morbidity and mortality and is associated with prolonged hospital stay and thus high resource consumption. Till date surgical intervention has been the main stay of management of chronic BPF. Our study was carried out to study the efficacy of sealants like Bioglue, Tissel glue and endobronchial devices like coils to close the BPFs through bronchoscopic interventions in those cases which failed to close with the conventional treatment regimen and progressed to chronicity. METHOD: This study was carried out in a tertiary care hospital. A total 25 patients of chronic BPF/air leaks were selected and subjected to bronchoscopic localization and subsequent intervention using sealants and coils. RESULTS: Total 25 patients with chronic BPF were treated with bronchoscopic interventions using glues, and coils.23 patients were males and 2 were females and 14 were postoperative while 11 patients were non operative. Only smaller fistulas were amenable to glues and coils while there was recurrence in patients with larger air leaks requiring surgical intervention. CONCLUSION: From this study it is concluded that non-operative bronchoscopic interventions to seal the air leaks are effective only in smaller air leaks i.e. alveolopleural fistula (APF). The larger air leaks like leaking stump and larger bronchopleural fistula have not got long lasting and encouraging results with sealants and endobronchial devices.

The versatility of lower eyelid blepharoplasty incision: In open reduction and fixation of zygomatic complex injuries.

INTRODUCTION: A ZYGOMATIC COMPLEX FRACTURE INCLUDES DISRUPTION OF THE FOUR ARTICULATING SUTURES: zygomaticofrontal, zygomaticotemporal, zygomaticomaxillary and zygomaticosphenoidal sutures. All zygomatic complex fractures involve the orbital floor and therefore an understanding of orbital anatomic features is essential for those treating these injuries. AIMS AND OBJECTIVES: To analyze the efficacy and shortcomings of this approach. To evaluate the adequacy, role of tarsorrhaphy, difficulties, role of steroid in postoperative edema control in lower lid blepharoplasty approach. MATERIALS AND METHODS: A total number of six patients were included in this study and all the patients were treated surgically under general anesthesia. All the patients were approached through lower eyelid blepharoplasty incision. The first skin crease in the lower eyelid region is selected for this incision. RESULTS: All patients were administered with steroid injection. Frost sutures were placed in four cases and tarsorrhaphy was done in two patients. Three cases encountered immediate mild edema and immediate scar formation. Late scar was present only in two patients with a follow up of three months. CONCLUSION: Lower eyelid blepharoplasty incision is an excellent, non complicated, simple procedure in the management of fractures in the infraorbital region, orbital floor, which occurs as a part of zygomatic complex fractures.

Increases in electroencephalogram and electromyogram variability are associated with an increased incidence of intraoperative somatic response.

BACKGROUND: sBIS, the variability of the Bispectral Index (BIS), sEMG, the variability of facial electromyogram power (EMG), and the Composite Variability Index (CVI) are 3 new measures of electroencephalogram and EMG variability. CVI is a single measure of the combined variability in BIS and EMG. We investigated whether increases in these variables are associated with intraoperative somatic responses. METHODS: This multicenter study included 120 patients undergoing elective, noncardiac surgery from 4 different sites. General anesthesia was maintained using propofol and remifentanil at 2 of the sites and sevoflurane and remifentanil at the 2 other sites. Propofol or sevoflurane was adjusted to maintain BIS between 45 and 60. Clinicians were blinded to CVI (v2.0) at all times, and remifentanil infusions were adjusted at the discretion of the clinician. The times of all intraoperative somatic events, defined as movement, grimacing, or eye opening, were recorded. Offline, the maintenance phase of each case was divided into consecutive, nonoverlapping, 10-minute segments. Segments were identified as containing a somatic event or containing no events. For each segment, mean sBIS, sEMG, and CVI and the heart rate (HR) range and mean arterial blood pressure range were calculated. To quantify how effectively each variable discriminated between somatic event segments and nonevent segments, we computed the area under the receiver operating characteristic (ROC) curve for each variable. Finally, we observed the time course of sBIS, sEMG, CVI, and the HR range before each somatic event and characterized the earliest time before the somatic event at which each variable was able to discriminate between the somatic events and a specified set of nonevents. RESULTS: The analysis included 33 somatic event segments and 829 nonevent segments from 105 surgical cases. The areas under the ROC curve (±SE) for sBIS, sEMG, and CVI were 0.83 ± 0.04, 0.92 ± 0.02, and 0.89 ± 0.03, respectively. The areas under the ROC curve for HR range and mean arterial blood pressure range were 0.77 ± 0.03 and 0.68 ± 0.05, respectively. CVI, sBIS, and sEMG all demonstrated higher average values before upcoming somatic events when compared with nonevents. HR range only showed a difference within a few seconds before the somatic event. CONCLUSION: sBIS, sEMG, and CVI, measures of electroencephalogram and EMG variability, increased when intraoperative somatic events occurred. sBIS, sEMG, and CVI discriminated between 10-minute segments that contained a somatic event and those segments that did not contain an event better than changes in HR and mean arterial blood pressure. Furthermore, CVI increases before somatic events began earlier than HR changes and may provide caregivers with an early warning of potentially inadequate antinociception.

Targeting urokinase and the transferrin receptor with novel, anti-mitotic N-alkylisatin cytotoxin conjugates causes selective cancer cell death and reduces tumor growth.

Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic N-alkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20(th) and 1/10(th) of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.

Prognostic factors for survival in systemic lupus erythematosus associated pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension (PH) is a rare but severe manifestation of systemic lupus erythematosus (SLE) that can ultimately result in death. The identification of factors that prognosticate survival in SLE-PH is necessary for appropriate monitoring, timing of therapeutics and lung transplantation. The primary objective of this study was to identify prognostic factors for survival in SLE-PH through review of the literature. The methodological quality of the prognostic studies was also evaluated. METHODS: A systematic review of the literature was performed to identify studies evaluating prognostic factors for survival in SLE-PH. Medline, EMBASE, CINAHL, and Cochrane Central Registry of Controlled Trials (inception - week 2 2010) were searched. A standardized abstraction form was used by two independent reviewers to extract prognostic factors. Methodological quality was evaluated using a validated quality index. RESULTS: Twenty-three observational studies from 375 citations were evaluated. Elevated mean pulmonary artery pressure, Raynaud's phenomenon, thrombocytopenia, plexiform lesion, infection, thrombosis, pregnancy, pulmonary vasculitis and anticardiolipin antibodies were associated with decreased survival. Lupus disease activity, nephritis and central nervous system disease were not associated with survival. The sample sizes were small and methodological quality of the studies was variable. CONCLUSION: This study summarizes factors that may be associated with decreased survival in SLE-PH. The small sample sizes and variable methodological quality preclude definitive conclusions. This study provides the groundwork for further research using large cohorts.