V-FAT study - A correlation between novel markers of obesity and coronary artery disease severity assessed by Syntax score in patients presenting with acute coronary syndrome.

Our aim was to evaluate the role of traditional versus newer markers of obesity, in risk assessment of CAD. 50 consecutive ACS patients and 20 controls were enrolled.Visceral and Subcutaneous fat (VFAT and SFAT) analysis was done using multi-slice abdominal MRI. Syntax score was calculated from coronary angiogram. In our study, BMI and Waist/Hip ratios showed poor correlation with Syntax score. VFAT and SFAT showed strong correlation with Syntax score (p-0.01,0.03) and a more significant correlation was noted with their areas at L3-L4 levels (p-0.01,0.05). Statistically significant ROC- area under curve was observed with Indexed SFAT.

Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071.

RATIONALE: Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and, in patients with Parkinson's disease (PD), to impairments in gait and balance and the resulting risks for falls. Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. OBJECTIVES: Here, we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that a M1 PAM amplifies such transient signaling and thereby rescues attentional performance. RESULTS: Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period. The post-dSAT period served to assess the capacity for recovering performance following a disruptive event. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, but also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d') in lesioned rats and facilitated the adoption of a more liberal response bias (B˝D) in all female rats. CONCLUSIONS: These findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.

Repetitive mild concussion in subjects with a vulnerable cholinergic system: Lasting cholinergic-attentional impairments in CHT+/- mice.

Previous research emphasized the impact of traumatic brain injury on cholinergic systems and associated cognitive functions. Here we addressed the converse question: Because of the available evidence indicating cognitive and neuronal vulnerabilities in humans expressing low-capacity cholinergic systems or with declining cholinergic systems, do injuries cause more severe cognitive decline in such subjects, and what cholinergic mechanisms contribute to such vulnerability? Using mice heterozygous for the choline transporter (CHT+/- mice) as a model for a limited cholinergic capacity, we investigated the cognitive and neuronal consequences of repeated, mild concussion injuries (rmCc). After five rmCc, and compared with wild type (WT) mice, CHT+/- mice exhibited severe and lasting impairments in sustained attention performance, consistent with effects of cholinergic losses on attention. However, rmCc did not affect the integrity of neuronal cell bodies and did not alter the density of cortical synapses. As a cellular mechanism potentially responsible for the attentional impairment in CHT+/- mice, we found that rmCc nearly completely attenuated performance-associated, CHT-mediated choline transport. These results predict that subjects with an already vulnerable cholinergic system will experience severe and lasting cognitive-cholinergic effects after even relatively mild injuries. If confirmed in humans, such subjects may be excluded from, or receive special protection against, activities involving injury risk. Moreover, the treatment and long-term outcome of traumatic brain injuries may benefit from determining the status of cholinergic systems and associated cognitive functions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

RATIONALE: Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned, DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT6 receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance of DL rats traversing rotating rods. OBJECTIVES: Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine. RESULTS: As before, vehicle-treated DL rats fell more frequently, committed more slips, and exhibited more movement stoppages than intact control rats. Repeated intermittent administration of rivastigmine and idalopirdine significantly improved the performance of DL rats. Rivastigmine alone also produced strong trends for reducing falls and slips. The combination treatment was more effective than rivastigmine alone in reducing stoppages and stoppage-associated falls. As before, idalopirdine treatment alone was ineffective. CONCLUSIONS: These results extend the prediction that the combined treatment with idalopirdine and an AChEI improves complex movement control and reduces the propensity for falls in patients with movement disorders. Because of the importance of finding better treatments for gait and balance deficits in PD, the present results may further motivate a clinical exploration of the usefulness of this combination treatment.

Massive Lymphedema Necessitating Disarticulation of Shoulder Joint Following Treatment for Carcinoma Breast.

We report a case of massive upper-limb edema necessitating disarticulation, in a cancer survivor who tended to ignore instructions regarding preventive exercises since 2002 after completion of her treatment for breast cancer. However, she was in a family situation where she was constrained to physically involve in daily chores. Consequently, she presented 14 years later with a lymphedematous arm which weighed over 31 kg, necessitating disarticulation. We highlight the role of preventive exercises in postmastectomy patients and also the efficacy of continuous nerve block techniques in preventing the development of phantom limb pain in cases of disarticulation and amputation. The role of family support for a working female cancer survivor in a country like India needs to be addressed. We salute her commitment to her family as also her grit and determination. Shoulder disarticulation was the last choice for this woman. We also want to highlight the role of the community in monitoring and preventing such disasters.

Reflective practices: meaningful recognition for healthy work environments.

Nurses' decisions about their intent to remain in the workforce are based on various factors. A healthy work environment in which work done well is recognised and appreciated contributes to nurses' satisfaction and better patient outcomes. This article examines the American Association of Critical-Care Nurses framework for a healthy work environment, focusing on standards for meaningful recognition. Reflective practice, which provides a self-analytical approach to appreciate and value one's work, is viewed as self-recognition. Neither boastful nor arrogant, reflective self-recognition is part of progression to professional maturity. It involves examining events at work continuously and systematically to learn, appreciate and move to higher levels of contribution in the workplace.

Validation of the Malayalam Version of Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale in Cancer Patients in the Regional Cancer Centre, Thiruvananthapuram, Kerala, India.

OBJECTIVE: The Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) is a 7-item self-report scale developed to identify pain which is of predominantly neuropathic origin. The aim of this study was to develop a Malayalam version of the LANSS and to test its validity and reliability in chronic pain patients. METHODOLOGY: We enrolled 101 Malayalam-speaking chronic pain patients who visited the Division of Palliative Medicine, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. The translated version of S- LANSS was constructed by standard means. Fifty-one neuropathic pain and fifty nociceptive pain patients were identified by an independent pain physician and were subjected to the new pain scale by a palliative care nurse who was blinded to the diagnosis. The "gold standard diagnosis" is what the physician makes after clinical examination. Its validation, sensitivity, specificity, and positive and negative predictive values were determined. RESULTS: Fifty-one neuropathic pain and fifty nociceptive pain patients were subjected to the Malayalam version of S-LANSS pain scale for validity testing. The agreement by Cohen's Kappa 0.743, Chi-square test P < 0.001, sensitivity 89.58, specificity 84.91, positive predictive value 84.31, negative predictive value 90.00, accuracy by 87.13, and likelihood ratio 5.94. CONCLUSION: The Malayalam version of S-LANSS pain scale is a validated screening tool for identifying neuropathic pain in chronic pain patients in Malayalam-speaking regions.

Hemicholinium-3 sensitive choline transport in human T lymphocytes: Evidence for use as a proxy for brain choline transporter (CHT) capacity.

The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP). Choline uptake capacity in T cells from CHT-OXP mice was two-fold higher than in wild type mice, mirroring the impact of CHT over-expression on synaptosomal CHT-mediated choline uptake. Monitoring T lymphocyte CHT protein and activity may be useful for estimating human CNS cholinergic capacity and for testing hypotheses concerning the contribution of CHT and, more generally, ACh signaling in cognition, neuroinflammation and disease.

Unresponsive Choline Transporter as a Trait Neuromarker and a Causal Mediator of Bottom-Up Attentional Biases.

Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENT The vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.

Cholinergic genetics of visual attention: Human and mouse choline transporter capacity variants influence distractibility.

The basal forebrain cholinergic projection system to the cortex mediates essential aspects of visual attention performance, including the detection of cues and the response to performance challenges (top-down control of attention). Higher levels of top-down control are mediated via elevated levels of cholinergic neuromodulation. The neuronal choline transporter (CHT) strongly influences the synthesis and release of acetylcholine (ACh). As the capacity of the CHT to import choline into the neuron is a major, presynaptic determinant of cholinergic neuromodulation, we hypothesize that genetically-imposed CHT capacity variation impacts the balance of bottom-up versus top-down control of visual attention. Following a brief review of the cognitive concepts relevant for this hypothesis, we describe the key results from our research in mice and humans that possess genetically-imposed changes in choline uptake capacity. CHT subcapacity is associated with poor top-down attentional control and attenuated (cholinergic) activation of right frontal regions. Conversely, mice overexpressing the CHT, and humans expressing a CHT variant hypothesized to enhance choline transporter function, are relatively resistant to challenges of visual attention performance. Genetic or environmental modulation of CHT expression and function may be associated with vulnerabilities for cognitive disorders.

A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats.

Kynurenic acid (KYNA) is a tryptophan metabolite that acts in the brain as an endogenous antagonist at multiple receptors, including glutamate and α7 nicotinic acetylcholine receptors. Increased levels of KYNA have been demonstrated in the brain of patients with a range of neurocognitive disorders, including schizophrenia, and are hypothesized to contribute to cognitive symptoms. Reducing KYNA levels by administering inhibitors of enzymes of the kynurenine pathway, particularly kynurenine aminotransferase II (KAT II), has been proposed as a treatment for such cognitive impairments. Here we report that administration of a systemically available KAT II inhibitor, PF-04859989, restores glutamate release events ("transients") evoked by pressure ejections of nicotine into the prefrontal cortex of rats exhibiting elevated KYNA levels. Nicotine-evoked glutamatergic transients can be reliably evoked and recorded after repeated pressure ejections of nicotine over 4-5 h. Systemic administration of l-kynurenine (100 mg/kg; i.p.) significantly increased frontal cortical KYNA levels and greatly attenuated the amplitude of nicotine-evoked glutamatergic transients. Systemic administration of PF-04859989 30 min prior to administration of l-kynurenine, but not when administered 30 min after l-kynurenine, restored glutamatergic transients recorded up to 75 min after the administration of the KAT II inhibitor. Furthermore, the KAT II inhibitor significantly reversed l-kynurenine-induced elevations of brain KYNA levels. The KAT II inhibitor did not affect nicotine-evoked glutamatergic transients in rats not pre-treated with l-kynurenine. Because PF-04859989 restores evoked glutamate signaling it therefore is a promising therapeutic compound for benefiting the cognitive symptoms of schizophrenia and other disorders associated with elevated brain KYNA levels.

Effects of hypoglycaemia on neurotransmitter and hormone receptor gene expression in laser-dissected arcuate neuropeptide Y/agouti-related peptide neurones.

Arcuate neuropeptide Y (NPY)/agouti-related pepide (AgRP) neurones regulate energy homeostasis, and express the putative glucosensor, glucokinase (GCK). The present study performed multi-transcriptional profiling of these neurones to characterise NPY, AgRP and GCK gene expression during intermediate insulin-induced hypoglycaemia, and to determine whether these transcriptional responses acclimate to repeated insulin dosing. We also examined whether these neurones express insulin, glucocorticoid and oestrogen receptor gene transcripts, and whether the levels of these receptor mRNAs are modified by insulin-induced hypoglycaemia. Individual NPY-immunoreactive neurones were laser-microdissected from the caudal arcuate nucleus after single or serial dosing with neutral protamine Hagedorn insulin (NPH), and evaluated by quantitative real-time reverse transcriptase-polymerase chain reaction for the assessment of neurotransmitter and receptor gene expression. Mean NPY and AgRP mRNA in harvested NPY neurones was unchanged or augmented, respectively, by one NPH dose, although repeated NPH administration up-regulated NPY, whereas AgRP gene transcripts were down-regulated. NPH elicited divergent modifications in the ERalpha and ERbeta mRNA content of sampled neurones. ERalpha transcripts were amplified by both acute and chronic NPH-induced hypoglycaemia, whereas ERbeta gene expression was unaltered during a single bout, but suppressed during recurring hypoglycaemia. Glucocorticoid receptor (GR) mRNA levels were increased by a single insulin dose, but unaffected by serial NPH dosing. Insulin receptor-beta chain (InsRb) gene transcripts were insensitive to acute NPH-induced hypoglycaemia, but repeated NPH inhibited this gene transcript. Neither acute nor recurring hypoglycaemia modified GCK mRNA levels in caudal hypothalamic arcuate nucleus (ARH) NPY/AgRP neurones, but baseline GCK transcription was suppressed by the latter. This evidence for the habituation of hypoglycaemic patterns of InsRb, GR and ERbeta gene transcription to serial NPH dosing implies that such treatment may alter reactivity of caudal ARH NPY/AgRP neurones to receptor ligands, and supports the need to determine whether adaptive changes in neuronal sensitivity to insulin, corticosterone and/or oestrogen cause up- versus down-regulation of NPY and AgRP neurotransmission, respectively, by this caudal ARH subpopulation during chronic hypoglycaemia.

Learning from each other: cross-cultural insights on palliative care in Indian and Australian regions.

This article presents the findings of a cross-cultural research project that explored similarities and differences between palliative care service provision in Kerala, India and South-East Queensland, Australia, to inform a process of mutual learning for service development. Three major points of difference that can inform this process of mutual learning were identified: 1) an understanding of the significance of honesty in information-giving to the patient, 2) recognition of the importance of palliative care specialists providing education to mainstream health professionals, and 3) appreciation of the need for palliative care to be cognizant of the socio-economic impact of dying-especially for families experiencing poverty-by embracing strategies for financial and material support. The findings highlight the effectiveness of a cross-cultural collaboration between health professionals and researchers in South-East Queensland, Australia and Kerala, India.

The palliative care movement in India: another freedom struggle or a silent revolution?

The message of palliative care in India has become a movement in several parts of India in a short span of time. The past two decades have seen palpable changes in the mindset of health care providers, and policy makers with respect to the urgency in providing palliative care. With a population of over a billion spread over a vast geo-political mosaic, the reach and reliability of palliative care programmes may appear staggering and insurmountable. Nonetheless we have reasons to be proud in that we have overcome several hurdles and is presently in a 'consolidation mode'. It is only a matter of time before the 'aam admi' has access to good palliative care. Easing narcotic licensing procedures, creation of standard operating procedures for morphine availability and the passing of the 'Palliative Care Policy' by the Government of Kerala are commendable milestones. We are today having more of 'silver linings' and less of 'dark clouds'.

Fatigue in cancer: a review of literature.

Fatigue is a common symptom of advanced cancer limiting one's activity and affecting the quality of life. It is a multidimensional symptom complex with subjective and objective components. Hence, its definition and assessment seems arbitrary, incomplete, and elusive. Components of fatigue often merge with other 'disease states' as anemia, depression and so on, compounding difficulty to assess it separately. Fatigue has a high prevalence rate, and lasts longer in chronic diseases like cancer. Its association with treatment modalities like chemotherapy, radiotherapy alongside the primary disease process makes it seemingly ubiquitous in many cases. Systemic manifestation of cancer causes excess demand on body resources on cell repair, uncontrolled growth with metabolite accumulation causing fatigue. Co-morbid conditions of organic and psychological nature causes fatigue. There are many assessment tools for fatigue with different uses and objectives, simple and reproducible tools like Brief Fatigue Inventory, Edmonton Symptom assessment scale seem feasible in everyday practice. Management of fatigue is not straightforward and rewarding. Although treatment of cause appears to be an attractive option, it is not possible in all cases. Therapeutic agents targeting cytokine load is in early stages of study and available results are not favorable. Specific measures aimed at pain relief, prevention/treatment of sepsis, management of depression, avoidance of drugs causing fatigue, restoring the metabolic profile are important. Methyl phenidate, megestrol, and modafinil are some drugs with promising effect to treat fatigue, though confirmatory studies are yet to be established. Non-pharmacological methods are also helpful. Forewarning patients on upcoming fatigue, active regular exercise, and stress management are some of them. Fatigue being a multidimensional entity, single mode of therapy is insufficient. Combined modality tailored to individual patient need and understanding may be the right way to battle this ill-understood symptom. This review article examines the etiopathogenesis and management strategies of fatigue in cancer.

Comparison of proximal isovelocity surface area method and pressure half time method for evaluation of mitral valve area in patients undergoing balloon mitral valvotomy.

BACKGROUND: The pressure half time (PHT) method is unreliable for measurement of mitral valve area (MVA) immediately after valvotomy. The proximal isovelocity surface area (PISA) method has been used to derive mitral valve area in patients with mitral stenosis. The aim of our study was to compare PISA method and PHT method in patients undergoing percutaneous balloon mitral valvotomy (BMV). METHODS: The PISA was recorded from the apex and MVA was calculated using continuity equation by the formula 2pir(2) Vr/Vm, where 2pir(2) is the hemispheric isovelocity area, Vr is the velocity at the radial distance "r" from the orifice, and Vm is the peak velocity. A plain angle correction factor (theta)/180 was used to correct the inlet angle subtended by leaflet tunnel as a result of leaflet doming. RESULTS: MVA calculated using PISA method (r = 0.5217, P < 0.0001, SE = 0.016) and PHT (r = 0.6652, P < 0.0001, SE = 0.017) correlated well with 2D method in patients with mitral stenosis before BMV. After BMV, MVA by PISA method correlated well with 2D planimetry (r = 0.5803, P < 0.0001, SE = 0.053) but PHT showed poor correlation (r = 0.1334, P = 0.199, SE = 0.036). The variability of measurement of MVA was most marked with PHT method in the post-BMV period. CONCLUSION: The PISA method correlates well with 2D planimetry in patients with mitral stenosis before and after BMV and is superior to the PHT method in the post-BMV period where the latter may be unreliable.

Continuous morphine infusions for cancer pain in resource-scarce environments: comparison of the subcutaneous and intravenous routes of administration.

Acute onset of severe pain in cancer patients may be due to multiple causes. Irrespective of the etiology, adequate analgesia has to be provided as quickly as possible. The standard practices of relieving pain by using syringe pumps (syringe drivers) or infusion pumps may not be feasible in resource-scarce developing nations where many cancer patients first present at advanced stages of disease for management. This study compared the efficacy of the subcutaneous and intravenous routes of morphine administration continuously using a simple and economic technique for cancer pain management. Both routes were found to be equally effective in producing good analgesia without side effects. The drip method is a cost-effective way of providing subcutaneous morphine infusion for cancer patients and is applicable for both inpatients and home care.