Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Developing a competency-based undergraduate logbook for pediatrics: Process and lessons.

With the first MBBS batch admitted under the new National Medical Commission (NMC) undergraduate curriculum entering pediatric clinical posting soon, creation of a Pediatric logbook in consonance with this competency-based curriculum was felt to be a need of the hour. No such document is yet available in the public domain. The logbook template, created after enormous brainstorming amongst authors, includes 176 Shows (S), Shows How (SH) and Perform (P) level competencies. These were further segregated into certifiable (23), affective domain (25) and clinic/field visits (9) leaving 51 as documentable competencies. The institutions may use this template to build their own institute-specific logbook based on the infrastructure, faculty strength, clinical patient load, student intake and preferred assessment method(s). It would also be worthwhile to integrate this with the internship logbook (and later the postgraduate one for students opting for post-graduation in pediatrics) to provide a longitudinal record of each student's trajectory of learning.

Multicentric Hospital-Based Surveillance of Pertussis Amongst Infants Admitted in Tertiary Care Facilities in India.

OBJECTIVE: To estimate the disease and economic burden of pertussis amongst hospitalised infants in India. DESIGN: Multicentric hospital-based surveillance study. PARTICIPANTS: Hospitalised infants with clinical suspicion of pertussis based on predefined criteria. OUTCOME MEASURES: Proportion of infants with laboratory-confirmed pertussis, economic burden of pertussis amongst hospitalised infants. RESULTS: 693 clinically suspected infants were recruited of which 32 (4.62%) infants had laboratory-confirmed pertussis. Progressive cough with post-tussive emesis (50%) and pneumonia (34%) were the common clinical presentations; apnea in young infants was significantly associated with pertussis. Infants with pertussis were more likely to be younger (median age 102.5 days vs.157 days) and born preterm (42.9% vs 24.5%). Almost 30% infants with pertussis had not received vaccine for pertussis with 50% of these infants aged less than 2 months. Pertussis was associated with higher costs of hospitalisation, pharmacy and loss of working days by caregivers as compared to non-pertussis cases. CONCLUSIONS: Younger infants, those born preterm and those inadequately immunised against pertussis are at higher risk of pertussis infection. Timely childhood immunisation and introduction of maternal immunisation for pertussis can help in reducing the disease burden.

Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe.

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week.

Hepatitis C virus re-treatment in the era of direct-acting antivirals: projections in the USA.

BACKGROUND: The introduction of oral direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment. However, a small percentage of patients fail to achieve sustained virologic response (SVR). Understanding the number of people who fail on DAAs and require re-treatment is important for budget impact and disease burden projections. AIM: To quantify the number of HCV patients who fail to achieve SVR on oral DAAs (NS5A vs. non-NS5A) and require re-treatment. METHODS: We used a mathematical model to simulate clinical management of HCV in the USA, which included the implementation of HCV screening, treatment, and disease progression. We simulated different waves of DAA treatment and used real-world data to extract SVR rates and market shares of available therapies. RESULTS: Our model projected that the number of people living without viraemia (i.e. cured) would increase from 0.70 million in 2014 to 1.78 million by 2020. Between 2014 and 2020, 1.50 million people would receive treatment with DAAs, of whom 124 000 (8.3%) are projected to fail to achieve SVR. Among those treatment failures, 66 600 (53.7%) patients would fail treatment with NS5A inhibitors and 69 600 (56.1%) would have cirrhosis. During the same period, 34 200 people would progress to decompensated cirrhosis and 27 300 would develop hepatocellular carcinoma after failing to achieve SVR. CONCLUSIONS: Even in the era of highly effective DAAs, a significant number of patients will fail to achieve SVR and will require re-treatment options. Timely and effective re-treatment is essential to prevent the long-term sequelae of HCV.

Systematic review: cost-effectiveness of direct-acting antivirals for treatment of hepatitis C genotypes 2-6.

BACKGROUND: The availability of direct-acting antivirals (DAAs) has dramatically changed the landscape of hepatitis C virus (HCV) therapy; however, the cost and budget requirements for DAA treatment have been widely debated. AIMS: To systematically review published studies evaluating the cost-effectiveness of DAAs for HCV genotype 2-6 infections, and synthesise and re-evaluate results with updated drug prices. METHODS: We conducted a systematic search of various electronic databases, including Medline, EMBASE, Cochrane library and EconLit for cost-effectiveness studies published from 2011 to 2016. Studies evaluating DAAs for genotypes 2-6 were included. Reported costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were abstracted. We re-estimated ICERs by varying the price of DAAs from $20 000 to $100 000, and estimated the threshold price at which DAA regimens would be deemed cost-effective (ICER≤$100 000/QALY). RESULTS: A total of 92 ICERs for 7 different DAA regimens from 10 published articles were included. Among the abstracted 92 ICERs, 20 were for genotype 2, 40 for genotype 3, 30 for genotype 4, 2 for genotype 5 and none for genotype 6; therefore, only genotypes 2-5 were analysed. At the discounted price of $40 000, 87.0% analyses found DAA regiments to be cost-effective, and 7.6% found to be cost-saving. The median threshold price below which DAAs would be deemed cost-effective was between $144 400 and $225 000, and cost-saving between $17 300 and $25 400. CONCLUSIONS: HCV treatment with DAAs is highly cost-effective in patients with HCV genotypes 2-5 at a $100 000/QALY threshold. Timely HCV treatment would be an optimal strategy from both a public health and economic perspective.

Physiological variables, psychosocial factors and age at menarche among Punjabi girls.

The term menarche signifying the onset of menstruation is merely one manifestation of puberty. The age at menarche has been getting earlier all over the world with varying rates. An average decline of about 4 months per decade has been reported from the United States and in Western Europe over the period 1830-1960, while that in Eastern Europe since the late nineteenth century. There have been reports that there is a fairly good correlation between the age of menarche of mothers' and their daughters'. The objective of this study was to find out the present age at menarche among Punjabi girls and correlate it with relevant variables. The age at menarche in the present study has been found to be significantly less as compared to data from the same region (Punjab, India). The decline in the mean age at menarche between the mothers and the daughters was statistically highly significant. There was a positive correlation between menarche and weight, height, triceps skinfold thickness, body mass index and maternal age at menarche. No significant correlation was obtained between menarche and income class and a negative correlation was obtained between menarche and birth order.

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories.

Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the site-specific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampal-specific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.

Identification of cell-type-specific promoters within the brain using lentiviral vectors.

The development of cell-type-specific mini-promoters for genetic studies is complicated by a number of issues. Here, we describe a general method for the relatively rapid screening of specific promoter activity in cell culture, in acute brain slice preparations and in vivo. Specifically, we examine the activity of an approximately 3 kb promoter region from the neuroactive peptide cholecystokinin (CCK) compared to the commonly used cytomegalovirus promoter. We find a high degree of cell-type selectivity in vivo using lentiviral approaches in rats and traditional transgenic approaches in mice. Appropriate colocalization of Cre-recombinase and CCK gene expression is found within the hippocampus, when the CCK promoter is driving either the expression of Cre-recombinase or green fluorescent protein. We also demonstrate fluorescent identification of CCK-positive interneurons that allows for cell-type-specific electrophysiologic studies in rats and mice. In conclusion, these studies identify a functional mini-promoter for the CCK gene and outline a novel and sensitive general method to test activity of selective promoters in vitro and in vivo. This approach may allow for the more rapid identification of specific promoters for use with transgenic animals, in genetically modified viruses, and in the design of targeted, therapeutic gene-delivery systems.

Perinatal mortality at a tertiary care hospital in Punjab.

The present report is a comparative analysis of perinatal mortality rate (PNMR) over two different periods of seven years each viz. 1982-1988 and 1989-1995. Data of all the perinatal deaths in babies born at Christian Medical College and Hospital, Ludhiana from January 1989 to December 1995 was collected. The cause of death was ascertained by a detailed history, clinical examination and whenever possible, by autopsy and analysed by modified Wigglesworth's classification. The PNMR during both the study periods was exactly the same i.e. 74/1000. There was a significant decline in the early neonatal mortality rate from 32/1000 to 25/1000. This was mainly due to improved survival of preterms as there were better life support measures available in the latter part of study period. In contrast, the still birth rate increased significantly from 42/1000 to 49/1000, thus neutralizing the fall of neonatal mortality. There was no change in the pattern of causes of death. Macerated still births occurring mainly in growth retarded babies and asphyxia remained the major causes of death. Mere provision of health services is not going to decrease PNMR. There is a need to educate 'the ultimate' consumers i.e. the women, for better utilization of these services. There is also an urgent need to sensitize and involve the medical practitioners imparting obstetrical services for solving these issues.

Reduced prefrontal cortical dopamine, but not acetylcholine, release in vivo after repeated, intermittent phencyclidine administration to rats.

Subchronic administration of phencyclidine to rats or monkeys produces prefrontal cortical cognitive dysfunction, as well as reduced frontal cortical dopamine utilization. In the current study, the effects of subchronic exposure to phencyclidine on dopamine and acetylcholine release in the prefrontal cortex were assessed, using in vivo microdialysis in conscious rats. Subchronic exposure to phencyclidine (5 mg/kg twice daily for 7 days) reduced both basal extracellular concentrations of dopamine as well as the increase in dopamine release produced by an acute phencyclidine challenge. The increase in dopamine release induced by a high potassium concentration in the perfusate tended to be reduced after subchronic phencyclidine treatment, while basal and evoked acetylcholine release was unaffected. These data demonstrate that altered dopamine turnover in subjects after subchronic exposure to phencyclidine is directly reflective of reduced release, and as such, represents a functionally relevant phenomenon.

Poisoning in children: Indian scenario.

The retrospective data on childhood poisoning from eight regional hospitals in India has been reviewed. The demographic features and types of poisonings encountered have been compared. The analysis of the data indicated that pediatric poisonings constituted 0.23-3.3% of the total poisoning. The mortality ranged from 0.64-11.6% with highest being from Shimla. Accidental poisoning was common involving 50-90% of children below 5 years of age and males outnumbered the females. Suicidal poisoning was seen after 13 years of age and was due to drugs and household chemicals. One of the hospitals in Delhi recorded a very high incidence (66.6%) of drug poisoning in children. The drugs consumed belonged to phenothiazines, antiepileptics and antipyretics. Iron poisoning was seen in younger children. Kerosene was one of the causes of accidental poisoning at all hospitals except Shimla and rural Maharashtra were probably wood charcoal is widely used. Pesticide poisoning was more prevalent in Punjab and West Bengal whereas plant poisoning was very common in Shimla. Significant number of snake envenomation has been recorded from rural Maharashtra. Other less common accidental poisonings in children included alcohol, corrosives, heavy metals, rodenticides, detergents and disinfectants. Thus various regions in the country showed some variation in types and frequency of childhood poisoning which could be attributed to different geographical and socio-economic background.

Prevalence of anemia among urban school children of Punjab.

OBJECTIVE: To assess the prevalence of anemia among urban school children of Punjab. DESIGN: Cross sectional study. SETTING: Urban schools of Ludhiana, Punjab. SUBJECTS: Two thousand school children of 5-15 years age. METHODS: Relevant history was taken and a complete physical examination done in all the children. Hemoglobin was estimated using cynmethemoglobin method and peripheral blood smears were also examined. Anemia was diagnosed when hemoglobin was less than 11 g/dl for children of 5-6 years age and 12 g/dl for more than 6 years age. RESULTS: Overall prevalence of anemia was 51.5%. Girls had a significantly higher prevalence of anemia except at 5 years and 10-12 years age. More menarcheal girls were anemic as compared to non-menarcheal ones. The prevalence of anemia was high (38%) even in higher socioeconomic groups. Nearly half (47.6%) of well nourished children were anemic. The mean Hb also was lower than expected normal values in both nutritional groups. Compared to non-vegetarians (38%), more vegetarians (65.9%) were anemic. The commonest blood picture seen was microcytic hypochromic (55.4%). CONCLUSIONS: The present study revealed a high prevalence of anemia among healthy urban school children of higher socio-economic classes. Vegetarians and girls, especially after menarche were more at risk to develop anemia.

Predictive utility of clinical and stool parameters in bacterial diarrhoea in children.

A prospective one year study was conducted on children between the ages of 1 month to 5 years hospitalised in the pediatric ward of Christian Medical College, Ludhiana, with the aim of determining the predictive utility of certain clinical and stool parameters in diagnosing bacterial diarrhoea. Among the 204 children enrolled in the study, fever was observed in 40% in both the culture positive and negative groups. Clinical features such as abdominal distension, vomiting and oliguria although had low positive predictive values, their negative predictive values were high. Among the stool parameters, watery consistency and pus cells > 5 HPF were significantly more often observed in culture positive cases. The presence of mucus and pus cells > 5 HPF had good sensitivity (70-80%) but poor specificity (27-40%), while the reverse was true of blood (sensitivity 23%, specificity 89%). Again the positive predictive values were uniformly low while the negative ones were high. In conclusion the clinical and stool parameters were found to be more useful by their absence than by their presence in excluding a positive stool culture.

Biophysical profile of blood pressure in school children.

The study was conducted in an industrial and prosperous city of Punjab to evaluate the biophysical profile of blood pressure (BP) in apparently healthy school children. A total of 2560 children between the ages of 5-15 years were enrolled. Their age, religion, dietary and family history were recorded. Weight and height of all children were measured and body mass index (BMI) calculated. A value of 2.26 or more was taken as obesity. BP measurements were made as per recommendations of the American Heart Association. Systolic as well as diastolic BP increased with age in both sexes, correlation coefficients being 0.59 and 0.6, respectively. A statistically significant linear relationship between BP and weight and height was noted. Children with BMI of > 2.26 had a significantly higher BP (P < 0.01). The mean BP did not vary among different religions. The BP of vegetarians and also non- vegetarians also did not differ. A family history of hypertension was associated significantly with elevated BP (p < 0.01). It is concluded that obesity and a family history of hypertension in children are associated with elevated BP and such children may be at risk for developing hypertension at a later date. They should be followed up and considered for modification of risk factors.