Click-train evoked steady state harmonic response as a novel pharmacodynamic biomarker of cortical oscillatory synchrony.

Sensory networks naturally entrain to rhythmic stimuli like a click train delivered at a particular frequency. Such synchronization is integral to information processing, can be measured by electroencephalography (EEG) and is an accessible index of neural network function. Click trains evoke neural entrainment not only at the driving frequency (F), referred to as the auditory steady state response (ASSR), but also at its higher multiples called the steady state harmonic response (SSHR). Since harmonics play an important and non-redundant role in acoustic information processing, we hypothesized that SSHR may differ from ASSR in presentation and pharmacological sensitivity. In female SD rats, a 2 s-long train stimulus was used to evoke ASSR at 20 Hz and its SSHR at 40, 60 and 80 Hz, recorded from a prefrontal epidural electrode. Narrow band evoked responses were evident at all frequencies; signal power was strongest at 20 Hz while phase synchrony was strongest at 80 Hz. SSHR at 40 Hz took the longest time (∼180 ms from stimulus onset) to establish synchrony. The NMDA antagonist MK801 (0.025-0.1 mg/kg) did not consistently affect 20 Hz ASSR phase synchrony but robustly and dose-dependently attenuated synchrony of all SSHR. Evoked power was attenuated by MK801 at 20 Hz ASSR and 40 Hz SSHR only. Thus, presentation as well as pharmacological sensitivity distinguished SSHR from ASSR, making them non-redundant markers of cortical network function. SSHR is a novel and promising translational biomarker of cortical oscillatory dynamics that may have important applications in CNS drug development and personalized medicine.

Splitting phonons: Building a platform for linear mechanical quantum computing.

Linear optical quantum computing provides a desirable approach to quantum computing, with only a short list of required computational elements. The similarity between photons and phonons points to the interesting potential for linear mechanical quantum computing using phonons in place of photons. Although single-phonon sources and detectors have been demonstrated, a phononic beam splitter element remains an outstanding requirement. Here we demonstrate such an element, using two superconducting qubits to fully characterize a beam splitter with single phonons. We further use the beam splitter to demonstrate two-phonon interference, a requirement for two-qubit gates in linear computing. This advances a new solid-state system for implementing linear quantum computing, further providing straightforward conversion between itinerant phonons and superconducting qubits.

Reversal of Feed Intolerance by Prokinetics Improves Survival in Critically Ill Cirrhosis Patients.

BACKGROUND AND AIMS: Feed intolerance (FI) is common in cirrhosis patients in intensive care units (ICU). Prokinetics are the first line treatment for FI but their efficacy and safety in critically ill patient with cirrhosis is unknown. We evaluated the role of prokinetics in reversal of FI and clinical outcomes. METHODS: Consecutive patients admitted in ICU developing new-onset FI, were randomized to receive either intravenous metoclopramide (Gr.A, n = 28), erythromycin (Gr.B, n = 27) or placebo (Gr.C, n = 28). FI was defined with the presence of 3 of 5 variables- absence of bowel sounds, gastric residual volume ≥ 500 ml, vomiting, diarrhoea and bowel distension. Primary end-point was complete resolution of FI (≥ 3 variables resolved) within 24-h and secondary end-points included resolution within 72-h and survival at 7-days. RESULTS: Of the 1030 ICU patients, 201 (19.5%) developed FI and 83 patients were randomized. Baseline parameters between the groups were comparable. Complete resolution at 24-h was higher in Gr.A (7.14%) and B (22.2%) than C (0%, p = 0.017). Overall, 58 (69.9%) patients achieved resolution within 72 h, more with metoclopramide (n = 24, 85.7%) and erythromycin (n = 25, 92.6%) than with placebo (n = 9, 32.1%, p < 0.001). The 7-day survival was better in patients who achieved resolution within 72-h (65.5 vs. 36%, p = 0.011) than non-responders. High lactate (OR-3.32, CI-1.45-7.70, p = 0.005), shock at baseline (OR-6.34, CI-1.67-24.1, p = 0.007) and resolution of FI within 72 h (OR-0.11, CI, 0.03-0.51, p = 0.04) predicted 7-day mortality. CONCLUSIONS: FI is common in critically-ill cirrhosis patients and non-resolution carries high mortality. Early recognition and treatment with prokinetics is recommended to improve short-term survival.

Gastrointestinal dysmotility is common in cirrhosis and higher incidence in critically ill patients. Promotility drugs are the first line of medication especially in ICU patients. In our study, we found that feed intolerance is present in nearly one in five critically ill cirrhosis and is associated with higher mortality. Patients who achieve resolution had an improved short-term survival. Prokinetic medications are safe in critically ill cirrhosis and help in early resolution of feed intolerance. Feed intolerance in critically ill cirrhosis should be recognized as an organ dysfunction and approaches for prevention and early diagnosis of feed intolerance could help in improving the outcomes in critical illness.

Management of internal carotid artery injury sustained during routine endoscopic sinus surgery.

A 49-year-old patient with a history of aspirin-exacerbated respiratory disease presented with carotid artery injury following revision functional endoscopic sinus surgery. Carotid artery injury is a rare but catastrophic complication of this surgery. The patient was transferred to our tertiary facility with interventional radiology for immediate management of the carotid artery injury. This case reaffirms that any surgery can have disastrous complications and highlights the importance of multidisciplinary management of complications such as carotid artery injury.

Dielectric relaxation and molecular interactions study of saccharides in aqueous solutions.

Time domain reflectometry (TDR) technique has been extensively used to study dielectric relaxation and solution properties of carbohydrates. Using TDR techninque, complex permittivity spectra of monosaccharides (d-fructose and d-xylose) and disaccharides (d-maltose monohydrates) were obtained in the frequency range of 10 MHz-50 GHz at various concentrations and temperatures. The static dielectric constant (ε0), dielectric constant at high frequency (ε∞), relaxation time (τ) and relaxation time distribution parameter (ß) extracted from the complex permittivity spectra using least squares fit method. The values of static dielectric constant were also verified by LCR meter by dielectric measurement in the frequency range of 20Hz to 2 MHz at 25 °C. The relaxation behavior of aqueous solutions of monosaccharides and disaccharides has been illustrated by using Cole-Davidson model. Activation enthalpy (ΔH), entropy (ΔS) and Kirkwood correlation factor have been determined to study extent of hydrogen bonding. This data might be useful in pharmaceutical, food processing industry and in solubility prediction method in aqueous solution.

Deviation from expected cognitive ability is a core cognitive feature of schizophrenia related to neurophysiologic, clinical and psychosocial functioning.

Cognitive functioning in schizophrenia is characterized by a generalized impairment in current cognitive ability based on traditional population-based norms. However, these norms assume a normal cognitive trajectory and do not directly account for illness-related declines from expected cognitive potential. Indeed, schizophrenia patients exhibit even greater deviation between their observed and expected cognitive functioning based on expanded norms that leverage premorbid variables resistant to illness-related features. The current study further quantified the extent to which illness-related features account for this deviation from expectation and assessed its relationship to neurophysiologic (mismatch negativity, P3a, theta oscillations), clinical, and psychosocial functioning in schizophrenia patients. Expected cognitive ability (PENN-CNB global cognition) in patients (n = 684) was calculated using healthy comparison subject (n = 660) weighted regression based on premorbid variables resistant to illness-related decline (demographics, single-word reading, parental education). The magnitude of any deviation between current (observed) and regression-predicted (expected) cognitive ability was calculated. Results indicated that 24% (n = 164) of the total patient population exhibited significant (≥-1.96 SD) deviation between observed and expected global cognitive ability. Interestingly, 20% of the total patient population (n = 136) had "normal" range cognitive performance when using traditional population-based norms, but also had significant deviation from expected cognitive ability. The magnitude of this deviation was associated with more severe neurophysiologic abnormalities, longer illness duration, higher levels of negative symptoms, and worse psychosocial functioning. Assessment of cognitive deviation is thus a complementary metric for characterizing the severity of illness-related cognitive declines in patients, while also reflecting the expression and severity of key endophenotypes of schizophrenia.

Mechanical thrombectomy for the treatment of acute ischaemic stroke following pulmonary lobectomy.

Acute ischaemic stroke is a devastating postoperative complication that significantly impacts upon a patient's quality of life. Endovascular retrieval of thromboembolic material from proximal cerebral arteries by mechanical thrombectomy is the new standard of care for patients presenting with a proximal artery occlusion. We report the case of a patient developing an acute ischaemic stroke following pulmonary lobectomy, who was transferred to the regional neurosciences unit, despite the absence of an established referral pathway, to undergo mechanical thrombectomy, with significant prognostic neurological benefit. We would advocate all cardiothoracic centres identify their regional neurosciences unit and initiate discussion to establish a referral pathway.

Decomposing the constituent oscillatory dynamics underlying mismatch negativity generation in schizophrenia: Distinct relationships to clinical and cognitive functioning.

Abnormalities in early auditory information processing (EAIP) contribute to higher-order deficits in cognition and psychosocial functioning in schizophrenia. A passive auditory oddball paradigm is commonly used to evoke event-related potential (ERP) measures of EAIP reflecting auditory sensory registration and deviance detection, including mismatch negativity (MMN) and P3a responses. MMN and P3a have been extensively studied in healthy subjects and neuropsychiatric patient populations and are increasingly used as translational biomarkers in the development of novel therapeutics. Despite widespread use, relatively few studies have examined the constituent oscillatory elements and the extent to which sensory registration and deviance detection represent distinct or intercorrelated processes. This study aimed to determine the factor structure and clinical correlates of these oscillatory measures in schizophrenia patients (n = 706) and healthy comparison subjects (n = 615) who underwent clinical, cognitive, and functional characterization and EEG testing via their participation in the Consortium of Genomics in Schizophrenia (COGS-2) study. Results revealed significant deficits in theta-band (4-7 Hz) evoked power and phase locking in patients. Exploratory factor analyses of both ERP and oscillatory measures revealed two dissociable factors reflecting sensory registration and deviance detection. While each factor shared a significant correlation with social cognition, the deviance detection factor had a unique relationship to multiple cognitive and clinical domains. Results support the continued advancement of functionally relevant oscillatory measures underlying EAIP in the development of precognitive therapeutics.

Molecular interactions in ethyl acetate-chlorobenzene binary solution: Dielectric, spectroscopic studies and quantum chemical calculations.

Dielectric studies using Time Domain Reflectometry method has been carried out on the binary solution of Ethyl acetate (EA) with Chlorobenzene (CBZ) over the entire composition range. Spectroscopic (FTIR and 13C NMR) signatures of neat EA, CBZ and their equimolar binary solution have also been recorded. The results of the spectroscopic studies favour the presence of (CBZ) CH⋯OC (EA), (EA) methylene CH⋯π electrons (CBZ) and (EA) methyl CH⋯Cl (CBZ) contacts which have been validated using quantum chemical calculations. Dimerization of CBZ has been identified. Presence of ß-clusters has been identified in all the solutions. Although EA and CBZ molecules have nearly equal molar volumes, CBZ molecules experience larger hindrance for the rotation than EA molecules. Very small excess dielectric constant (εE) values may be correlated with weak heteromolecular forces and/or closed heteromolecular association.

Cholangicarcinoma Presenting as a Sister Mary Joseph Nodule.

Sister Mary Joseph nodules represent metastatic cancer of the umbilicus. More than half of these cases are attributable to gastrointestinal malignancies including gastric, colonic, and pancreatic cancer. In addition, gynecologic (ovarian, uterine cancer), unknown primary tumors, and, rarely, bladder or respiratory malignancies may cause umbilical metastasis. We report the case of a Sister Mary Joseph nodule originating from a hilar cholangiocarcinoma. Umbilical nodules should prompt clinical evaluation, as these tumors are usually associated with poor prognosis.

Maternal dexamethasone exposure ameliorates cognition and tau pathology in the offspring of triple transgenic AD mice.

Dysregulation of stress hormones, such as glucocorticoids, in adult life increases the risk to develop Alzheimer's disease (AD). However, the effect of prenatal glucocorticoids exposure on AD development in the offspring remains unknown. We studied how gestational dexamethasone exposure influences the AD-like phenotype in the offspring of triple transgenic AD mice (3 × Tg). To this end, female mice received dexamethasone or vehicle during the entire pregnancy time in the drinking water. Offspring from vehicle-treated 3 × Tg (controls) were compared with offspring from dexamethasone-treated 3 × Tg later in life for their memory, learning ability and brain pathology. Compared with controls, offspring from dexamethasone-treated mothers displayed improvement in their memory as assessed by fear conditioning test, both in the cue and recall phases. The same animals had a significant reduction in the insoluble fraction of tau, which was associated with an increase in autophagy. In addition, they showed an activation of the transcription factor cellular response element-binding protein and an increase in brain-derived neurotrophic factor and c-FOS protein levels, key regulators of synaptic plasticity and memory. We conclude that dexamethasone exposure during pregnancy provides long-lasting protection against the onset and development of the AD-like phenotype by improving cognition and tau pathology.

Reversible brainstem dysfunction from spinal arterio-venous fistula.

A 45-year-old man presented with subacute onset of ataxia, diplopia, urinary retention and paraparesis. MR scan of brain showed abnormal T2 hyperintense signal within the cervical cord, medulla and lower pons and vascular appearances suggesting an arterio-venous fistula. The fistula was surgically explored and successfully disconnected with good clinical outcome. Brainstem or cervical dural arterio-venous fistulae more typically present as a myelopathy; only a handful of cases have presented with brainstem dysfunction. This is a rare but reversible cause of subacute brainstem dysfunction.

Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease.

5-Lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD) and in vivo modulates the amyloidotic phenotype of amyloid precursor protein transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue, we used a genetic and a pharmacological approach by generating 3 × Tg mice deficient for 5LO and administering 3 × Tg mice with a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life, these mice had a significant reduction of Aß and tau pathology. Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this protein as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.

A pilot study to evaluate pharmaceutical pictograms in a multispecialty hospital at dehradun.

Pharmaceutical pictograms have the potential to play an important role in optimizing compliance in the illiterate patient population. Pictograms may improve warning comprehension for those with visual or literacy difficulties and can sometimes be recognized and recalled far better than words. The main purpose of this study is to determine whether these pictograms can be effectively understood by illiterate patients, who otherwise cannot read the instructions given on their prescription order. In this study, 10 pharmaceutical pictograms were evaluated in patients attending the outpatient department of the Shri Mahant Indresh Hospital, a multispecialty, referral hospital in Dehradun (Uttarakhand). Understanding of pictograms by patients before and after interpretation was noted and follow-up interpretation was also noted. Results of the study showed that prior to explanation, the majority of the patients were unable to interpret the pictograms correctly but after explanation of their meaning, interpretation by them showed a marked improvement, indicating the need of using pictograms along with verbal reinforcement. The study also highlighted poor patient follow-up, a major cause of patient non-compliance, often leading to a poor therapeutic outcome of the prescribed medication order. Such problems can be taken care of by an active participation by healthcare professionals.

An extended role for CT in the emergency diagnosis of malignant spinal cord compression.

AIM: To evaluate the usefulness of computed tomography (CT) for triaging between urgent transfer to a neurosurgical unit and delayed magnetic resonance imaging (MRI) in the local hospital. MATERIALS AND METHODS: Radiologists blinded to the MRI findings scored CT images from 1-5 using a novel grading system based on the degree of cord compression observed in 44 patients. Seventy separate levels were scored. The observers' CT scores were compared with the MRI findings. All scoring radiologists were specialist registrars at different stages of training. RESULTS: Agreement between CT and MRI scores for metastatic spinal cord compression (MSCC) were high with Cohen's weighted Kappa score 0.70 (p<0.001, 95% CI 0.65 to 0.75). CT has a sensitivity of 89% and specificity of 92% for MSCC. Half the false-positive and false-negative results came from a single junior radiologist who would not normally report CT or MRI studies unsupervised. The best CT-MRI agreement was from the most senior trainee radiologist. CONCLUSIONS: Spinal findings on routine staging whole-body CT combined with clinical findings are sufficient to determine which patients with MSCC can safely wait for MRI the next working day at the local hospital and those who need emergency transfer to a neurosurgical unit for MRI and possible surgical decompression.

A study of practical parameters and their relative importance as perceived by various stakeholders in clinical trials.

A contract research organization (CRO) is a company which conducts a Good Clinical Practice (GCP) in clinical trial. There are literally hundreds of CROs worldwide employing a workforce of nearly 100,000 professionals. The project proposes the study of practical parameters and their relative importance as perceived by the various stakeholders in clinical trials. The survey was conducted in Bangalore and New Delhi. Primary market data was obtained by primary market research which included 80 clinical trial stakeholders by having a preliminary communication with them, followed by administering a questionnaire along with prior permission. There were 15 Sponsors/ CROs, 27 Investigators /Monitors and 38 Ethics committee members involved in the study. It was shown from the study that a clinical investigator involved in a clinical trial is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of the subjects under the investigator's care; and for the control of drugs under investigation. It was also shown from the study that the sponsors of a clinical trial carry the ultimate responsibility for the initiation, management and financing of the clinical trial. The study has identified a specific training need at the level of the individual stakeholder to perform a particular job function and to identify the actual practical parameters in the Indian context important for the conduction of clinical trials (GCP) with respect to the different stakeholders, to determine the relative importance of these parameters as perceived by various stakeholders involved in clinical trials, and to identify the relative contributions of different stakeholders to the success/ satisfactory conduct of a clinical trial.

Dietary survey and total dietary fiber intake in patients with irritable bowel syndrome attending a tertiary referral hospital.

BACKGROUND: Based on their chemical extraction, dietary fibers are classified into crude fibers and total dietary fibers (TDF). TDF gives the best estimate of fiber content in the diet. Whereas data on intake of crude fibers are available, there is a lack of data on intake of TDF in patients with irritable bowel syndrome (IBS). AIM: We assessed the TDF and its source in the diet of patients with IBS and healthy controls (HC). METHODS: Based on their predominant symptoms, 81 patients with IBS (according to Rome II criteria) were categorized into constipation-predominant (IBS-C, n=48), diarrhea-predominant (IBS-D, n=16) and mixed type (IBS-M, n=17). Information was collected on fiber supplementation and preference for high-fiber food. A pretested, open-ended, semi-quantitative food frequency questionnaire was used to collect dietary information on food groups and TDF. Age- and sex-matched healthy individuals (n=89) were recruited as HC. The mean (SD) age of patients and HC was 36.5 (11.4) years (59 men), and 36 (12) years (62 men), respectively. RESULTS: Thirty-nine patients (48%) were taking medicinal fiber supplements, of which 28 patients were taking supplements daily (2.10 [0.84] teaspoon full). The mean daily TDF intake was 51.7 (23.1) g vs. 52.3 (21.6) g for patients and HC, respectively (p=0.8). The intake of TDF was similar in patients having less (n=41) or more (n=40) preference for fiber-rich foods (55 [23] g vs. 47 [22] g, p=0.16). The daily mean cereal intake in patients was significantly lower than that in HC (322 g vs. 404 g, p=0.001). However, consumption of fruits (150 g vs. 80 g, p=0.001) and vegetables (348 g vs. 219 g, p=0.006) was higher in patients in comparison with HC. There was a positive correlation between TDF with cereals (p=0.001), pulses (p=0.001), vegetables and fruits (p=0.033) in patients with IBS but only with cereals (p=0.001) in HC. CONCLUSION: The intake of TDF in patients with IBS and HC is much higher than the dietary recommendation for healthy Indians. Patients with IBS consumed more fruits and vegetables rather than cereals as compared with HC.