Thromboplastin standards

The Prothrombin Time (PT) test is used for monitoring of treatment with Vitamin K-antagonists (VKA). The result of the PT test should be expressed as the International Normalized Ratio (INR). Calculation of INR is based on the availability of International Standards (IS) for thromboplastin and a calibration model. Calibration of a new PT test system is performed with the appropriate IS and fresh plasma samples of healthy (normal) volunteers and patients treated with VKA. The calibration model is based on the assumption of a linear relationship between the log(PT)'s obtained with the new PT system and the reference IS for both normal and patients' samples. Patients' samples for calibration should be selected by rejecting samples beyond the 1.5–4.5 INR range. Outliers should be rejected defined as points with a perpendicular distance greater than three residual standard deviations from the line of relationship. Selection of patients' samples and rejection of outliers result in a reduction of the between-laboratory variation of calibration. In addition to monitoring of VKA, the PT is used for management of patients with chronic liver disease. Likewise, INR_liver should be based on calibration with an IS using samples from patients with chronic liver disease.     

Reference data for the Ruff Figural Fluency Test stratified by age and educational level

The Ruff Figural Fluency Test (RFFT) was developed to avoid the difficulties that were encountered in earlier tests of figural fluency. Although the test characteristics of the RFFT seem to be good and it is a valuable addition to neuropsychological assessments, reference data are still scarce. To this aim, we required 2,404 community dwelling persons in Groningen, The Netherlands to perform the RFFT. All 1,651 persons with a complete RFFT and known educational level formed the reference sample. Their age ranged from 35 to 82 years and their educational level from primary school to university grade. Ninety-six percent of the persons were of Western European descent. All tests were analyzed by two independent examiners and subsequently three measures were calculated: number of unique designs, number of perseverative errors and error ratio. The main finding was that performance on the RFFT was dependent on age and educational level. This was not only observed in older persons but also in young and middle-aged persons. Reference data for the three RFFT measures are presented in groups of five years of age ranging from 35-39 years to 75 years or older.     

Air travel and incidence of pneumothorax in lymphangioleiomyomatosis

Background

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease of women characterized by multiple lung cysts leading to respiratory insufficiency and frequent pneumothorax (PT). Air travel (AT) could increase the risk of PT in LAM through rupture of subpleural cysts induced by atmospheric pressure changes in aircraft cabin. To determine whether AT increases the risk of PT in LAM, we performed a retrospective survey of members of European LAM patient associations. A flight-related PT was defined as occurring ≤30?days after AT.

Results

145 women reported 207 PT. In 128 patients with available data, the annual incidence of PT was 8% since the first symptoms of LAM and 5% since LAM diagnosis, compared to 0.006% in the general female population. Following surgical or chemical pleurodesis, the probability of remaining free of PT recurrence was respectively 82, 68, and 59% after 1, 5 and 10?years, as compared to only 55, 46 and 39% without pleurodesis (p?=?0.026). 70 patients with available data performed 178 AT. 6 flight-related PT occurred in 5 patients. PT incidence since first symptoms of LAM was significantly higher ≤30?days after AT as compared to non-flight periods (22 versus 6%, risk ratio 3.58, confidence interval 1.40–7.45).

Conclusions

The incidence of PT in LAM is about 1000 times higher than in the general female population, and is further increased threefold after AT. Chemical or surgical pleurodesis partly reduces the risk of PT recurrence in LAM.

     

Neuroanatomical Correlates of Intelligence in Healthy Young Adults: The Role of Basal Ganglia Volume

Background

In neuropsychiatric diseases with basal ganglia involvement, higher cognitive functions are often impaired. In this exploratory study, we examined healthy young adults to gain detailed insight into the relationship between basal ganglia volume and cognitive abilities under non-pathological conditions.

Methodology/Principal Findings

We investigated 137 healthy adults that were between the ages of 21 and 35 years with similar educational backgrounds. Magnetic resonance imaging (MRI) was performed, and volumes of basal ganglia nuclei in both hemispheres were calculated using FreeSurfer software. The cognitive assessment consisted of verbal, numeric and figural aspects of intelligence for either the fluid or the crystallised intelligence factor using the intelligence test Intelligenz-Struktur-Test (I-S-T 2000 R). Our data revealed significant correlations of the caudate nucleus and pallidum volumes with figural and numeric aspects of intelligence, but not with verbal intelligence. Interestingly, figural intelligence associations were dependent on sex and intelligence factor; in females, the pallidum volumes were correlated with crystallised figural intelligence (r = 0.372, p = 0.01), whereas in males, the caudate volumes were correlated with fluid figural intelligence (r = 0.507, p = 0.01). Numeric intelligence was correlated with right-lateralised caudate nucleus volumes for both females and males, but only for crystallised intelligence (r = 0.306, p = 0.04 and r = 0.459, p = 0.04, respectively). The associations were not mediated by prefrontal cortical subfield volumes when controlling with partial correlation analyses.

Conclusions/Significance

The findings of our exploratory analysis indicate that figural and numeric intelligence aspects, but not verbal aspects, are strongly associated with basal ganglia volumes. Unlike numeric intelligence, the type of figural intelligence appears to be related to distinct basal ganglia nuclei in a sex-specific manner. Subcortical brain structures thus may contribute substantially to cognitive performance.     

Studies on nucleotide and receptor regulation of Gi proteins: effects of pertussis toxin

In intact membranes as well as after reconstitution into phospholipid vesicles, pertussis toxin (PT)-mediated ADP-ribosylation of G proteins causes loss of receptor-mediated regulation of effectors and/or G protein-mediated regulation of receptor binding. Studies were carried out to test which of several discrete steps known to constitute the basal and receptor-stimulated regulatory cycles of Gi proteins are affected by PT. Experiments with the Gs-deficient Gi-regulated adenylyl cyclase of cyc- S49 cell membranes indicated that PT blocks Gi activation by GTP without affecting GDP dissociation or GTP binding to a major extent. This suggested that the block lies in the transition of inactive GTP-Gi to active GTP-Gi (G to G* transition). Experiments with purified Gi in solution and after incorporation into phospholipid vesicles showed that PT does not increase or decrease the intrinsic GTPase activity of Gi. Experiments in which Gi was incorporated into phospholipid vesicles with rhodopsin, a receptor that interacts with Gi to stimulate the rate of guanosine 5'-O-(3-thio)triphosphate binding and GTP hydrolysis, indicated that PT does not affect the basal GTPase activity of Gi, but blocks its activation by the photoreceptor. Taken together the results indicate that PT-mediated ADP ribosylation has two separate effects, one to block the interaction of receptor with Gi and another to impede the GTP-induced activation reaction from occurring, or that PT has only one effect, that of blocking interaction with receptors. In this latter case the present results add to a mounting series of data that are consistent with the hypothesis that unoccupied receptors are not inactive, but exhibit a basal agonist-independent activity responsible for the various effects of GTP observed on G protein-coupled effector functions in intact membranes.     

Neuropsicología y diagnóstico temprano

The presence of histopathological lesions characteristic of Alzheimer's disease, senile plaques and neurofibrillar degeneration in the brains of cognitively normal individuals has been well documented in several longitudinal clinicopathological studies over the last two decades. Clinical and pathological epidemiological data suggest that Alzheimer's disease can begin to develop almost a decade before the first clinical manifestations appear. The present article reviews the studies investigating cognitive alterations before the disease manifests. All these studies reveal the presence of alterations in preclinical phases in cognitive functions other than memory, such as those related to attention, processing speed and verbal fluency. Assessment of memory with tools sensitive to hippocampal memory impairment is recommended. The best predictor is having each individual's baseline performance, which can then be used for comparison with subsequent performance. Once reduced performance is detected (even when within the “normal” range), affected persons should be referred to specific units able to diagnose the disease in the early stages.     

The melanophore aggregating response of isolated fish scales: a very rapid and sensitive diagnosis of whooping cough

Pertussis toxin (PT) has been found to block noradrenaline-induced pigment aggregation in fish melanophores, and, based on this, a rapid and highly sensitive assay for PT was developed. Some preliminary results have also indicated that it may be possible to detect PT-like activity in saliva samples from patients with clinically suspected pertussis. In the present study the diagnostic value of the fish melanophore method was evaluated in 70 patients suspected of having pertussis; culture, serology and physician diagnosis were used as reference methods. In 60 of the patients, pertussis was verified by at least one of the reference methods. The melanophore test showed PT-like activity in saliva samples from 58 of the patients. Three patients with reference-verified pertussis showed no PT-like activity in the test; among these, one patient had been immunized and had also been treated with erythromycin during 3 days immediately prior to visiting the hospital. The melanophore test has three major advantages: it allows detection of pertussis in the early and curable stage of the disease; it takes only 2 h to perform; and it requires no sophisticated equipment.     

Datos normativos del test Barcelona revisado-abreviado para personas mayores cognitivamente activas

IntroductionNeuropsychological assessment is mandatory in order to identify cognitive changes that occur during either normal or pathological aging. However, normative data adapted to the characteristics of the population are needed in order to reduce the probability of false diagnoses of cognitive impairment. The aim of the present work was to compute normative data for cognitively active elderly people attending a University course for the elderly.Materials and methodsAn analysis was performed on the data from 87 participants (70.9% women) with a mean age of 66.73 years who undertook the abbreviated- revised Barcelona test (test de Barcelona revisado-abreviado). Normative data were calculated using linear regressions controlling for age, gender, and years of education. Adjusted normative data were compared with normative data available from the test manual and obtained from the general population.ResultsYears of education and gender showed the highest weights in the regression model. Normative data for cognitively active older adults showed a different number of low scores compared to normative data from the general population. The number of low scores were related to years of education and general cognitive functioning.ConclusionsNormative data obtained from cognitively active older people could help identify more accurately the cognitive functioning of cognitively active older people than do normative data obtained from the general population.     

The Location Learning Test as a measure of spatial memory: applicability of a modified administration procedure and normative data

The Location Learning Test is a neuropsychological test that can be used to assess memory for object locations. The test has originally been developed for the assessment of visuo-spatial memory impairment in patients with dementia. However, ceiling effects may be present in other patient groups. This study has examined the applicability of a modified administration procedure with a shorter presentation duration and longer delay. The test was administered in a group of stroke patients (n = 105), a group of patients with diabetes (n = 93), as well as a group of healthy volunteers (n = 97). The results indicate that the Location Learning Test can be used to discriminate the diabetes and stroke patients from the control group. Furthermore, differences between patients with a left and a right-hemisphere stroke were found. The test has a high correlation with another memory test. The performance of the group healthy volunteers was used to calculate normative data for use in clinical practice.     

ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

Background

1) To report site-specific normative values by age, sex and educational level for four components of the 10/66 Dementia Research Group cognitive test battery; 2) to estimate the main and interactive effects of age, sex, and educational level by site; and 3) to investigate the effect of site by region and by rural or urban location.

Methods

Population-based cross-sectional one phase catchment area surveys were conducted in Cuba, Dominican Republic, Venezuela, Peru, Mexico, China and India. The protocol included the administration of the Community Screening Instrument for Dementia (CSI 'D', generating the COGSCORE measure of global function), and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) verbal fluency (VF), word list memory (WLM, immediate recall) and recall (WLR, delayed recall) tests. Only those free of dementia were included in the analysis.

Results

Older people, and those with less education performed worse on all four tests. The effect of sex was much smaller and less consistent. There was a considerable effect of site after accounting for compositional differences in age, education and sex. Much of this was accounted for by the effect of region with Chinese participants performing better, and Indian participants worse, than those from Latin America. The effect of region was more prominent for VF and WLM than for COGSCORE and WLR.

Conclusion

Cognitive assessment is a basic element for dementia diagnosis. Age- and education-specific norms are required for this purpose, while the effect of gender can probably be ignored. The basis of cultural effects is poorly understood, but our findings serve to emphasise that normative data may not be safely generalised from one population to another with quite different characteristics. The minimal effects of region on COGSCORE and WLR are reassuring with respect to the cross-cultural validity of the 10/66 dementia diagnosis, which uses only these elements of the 10/66 battery.     

Polymorphism of the Serotonin Receptor Type 2A (5-HTR2A) Gene and Verbal Fluency in Normalcy and in Schizophrenia

To study the effect of the serotonergic brain system on verbal fluency (i.e., the ability to rapidly extract necessary words from the internal vocabulary), the T102C polymorphism of the serotonin receptor type 2A (5-HTR2A) gene was tested for association with verbal fluency in 108 patients with schizophrenia or disorders of the schizophrenic spectrum and 97 mentally healthy individuals. A significant association was observed only in male schizophrenics (n = 67), with homozygotes A2A2 having lower verbal fluency. The results do not support the association between the 5-HTR2A polymorphism and verbal fluency in normalcy, and agree with the assumed contribution of genotype A2A2 to the severity of schizophrenia.     

Developmental Trajectories of Girls' BMI Across Childhood and Adolescence

This study describes qualitatively distinct trajectories of BMI change among girls participating in a longitudinal study of non‐Hispanic, white girls (n = 182) and their parents, assessed at daughters' ages 5, 7, 9, 11, 13, and 15 years. Height, weight, body fat, fasting blood glucose and lipids, blood pressure, waist circumference, and pubertal status were measured, and participants self‐reported dietary, physical activity, and television (TV) viewing patterns. Growth mixture models were used to model heterogeneity in girls' BMI trajectories over 10 years. Statistical support was strongest for four distinct BMI trajectories: (i) upward percentile crossing (UPC; n = 25, 14%); (ii) delayed downward percentile crossing (DDPC; n = 37, 20%); (iii) 60th percentile tracking (60PT; n = 52, 29%); and (iv) 50th percentile tracking (50PT; n = 68, 37%). Girls in the UPC group had more metabolic risk factors at age 15 years, even after adjusting for concurrent weight status. Girls in the UPC group had mothers with the highest BMIs at study entry and were breast‐fed for a shorter duration. This novel approach for examining differences in growth trajectories revealed four distinct BMI trajectories that predicted adolescent metabolic health outcomes in girls. The present study provides support for BMI monitoring in girls and for the potential utility of combining data on BMI tracking with data on familial characteristics for the early identification of girls at elevated risk for obesity and metabolic syndrome.     

A validation study of appropriate phonological verbal fluency stimulus letters for use with croatian speaking individuals

The aim of this study is to determine the word frequency for all thirty letters of the Croatian alphabet and to collect normative data for the letter fluency task in Croatian speakers. Ninety two healthy participants were given each of the Croatian letters, and asked to generate as many words as possible in 60 seconds for each letter Results suggested that participants generated most frequently words starting with the letters as follows: "K", "P", "S" and "M".     

Verbal fluency in adults diagnosed with attention-deficit hyperactivity disorder (ADHD) in childhood

It has been increasingly believed that attention-deficit hyperactivity disorder (ADHD) is a disorder with lifelong course associated with cognitive difficulties including among others, language production, verbal learning, and verbal fluency. However, research is limited to children and adolescents, and very few researchers have examined the impact of ADHD in adulthood on the cognitive domain. The aim of the present study is to examine the performance of adults, diagnosed with ADHD in childhood, on semantic and phonemic verbal fluency tasks. It is hypothesized that adults with ADHD will perform worse on both tasks than matched controls. Sixty university students (30 diagnosed with ADHD in childhood and 30 matched controls) of mean age 20.5 participated in the study. They all completed two verbal fluency tasks. The ADHD group had statistically significant lower scores than the non-ADHD group on the phonemic, but not the semantic task. The study provides some evidence that ADHD in childhood has a negative impact on adults’ phonemic verbal fluency. This finding could be probably explained by the fact that phonemic fluency is considered more cognitively demanding and impacting more on the frontal lobe functions, known to be impaired in ADHD, than semantic fluency.     

Complex Prospective Memory in Adults with Attention Deficit Hyperactivity Disorder

Objectives

Attention deficit hyperactivity disorder (ADHD) in adults has been associated with disturbances of attention and executive functions. Furthermore, impairments of verbal and figural retrospective memory were reported. However, little is known about the effects of ADHD on prospective memory, the execution of delayed intentions in the future.

Methods

The present study compared the performance of 45 adult patients with ADHD not treated with stimulant medication with the performance of 45 matched healthy individuals on a paradigm of complex prospective memory which measured task planning, plan recall, self-initiation and execution. Furthermore, the contribution of other cognitive functions to prospective memory functioning was assessed, including measures of attention, executive functions and memory.

Results

A large-scale impairment could be observed in task planning abilities in patients with ADHD. Only negligible to small effects were found for plan recall, self-initiation and execution. Inhibition was identified to contribute significantly to performance on task planning.

Conclusions

The present findings suggest that four cognitive components contribute to the performance of prospective memory. Impairments of prospective memory mainly emerged from deficient planning abilities in adults with ADHD. Implications on behavioral based intervention strategies are discussed.     

Phyllodes tumour: cytologic and histologic presentation of 22 cases, and immunohistochemical demonstration of p53

A retrospective study of 22 cases of phyllodes tumour (PT) was undertaken to evaluate the potential value of fine needle aspiration (FNA) cytology in the diagnosis of benign and borderline PT. Histological material was available from 12 patients with typical benign PT (group 1), six patients with less typical changes (group 2) and four cases of borderline PT (group 3). Cytological presentation of PT in these cases was similar to that described by other cytologists, although abundant cellular material was obtained in only eight FNAs, naked nuclei were present in nine cases only, and atypical or suspicious cytological features were found in seven cases. Comparative analysis of p53 was made in nine patients with PT, five cases with other benign breast lesions and five with malignant lesions. p53 reaction was positive in five of nine patients with PT (all cases from groups 2 and 3), compared with two of five cases of carcinoma. p53 was negative in all patients with PT from group 1 and the five other benign cases. We suggest that cytopathologists should be careful when a myxoid stromal component is present in cytological smears.     

High Rates of Ofloxacin Resistance in Mycobacterium tuberculosis among Both New and Previously Treated Patients in Tamil Nadu,South India

Periodic drug resistance surveillance provides useful information on trends of drug resistance and effectiveness of tuberculosis (TB) control measures. The present study determines the prevalence of drug resistance among new sputum smear positive (NSP) and previously treated (PT) pulmonary TB patients, diagnosed at public sector designated microscopy centers (DMCs) in the state of Tamil Nadu, India. In this single-stage cluster-sampling prevalence survey, 70 of 700 DMCs were randomly selected using a probability-proportional to size method. A cluster size of 24 for NSP and a varying size of 0 to 99 for PT cases were fixed for each selected DMC. Culture and drug susceptibility testing was done on Lowenstein-Jensen medium using the economic variant of proportion sensitivity test for isoniazid (INH), rifampicin (RMP), ofloxacin (OFX) and kanamycin (KAN). Human Immunodeficiency Virus (HIV) status was collected from patient records. From June 2011 to August 2012, 1524 NSP and 901 PT patients were enrolled. Any RMP resistance and any INH resistance were observed in 2.6% and 15.1%, and in 10.4% and 30% respectively in NSP and PT cases. Among PT patients, multi drug resistant TB (MDR-TB) was highest in the treatment failure (35%) group, followed by relapse (13%) and treatment after default (10%) groups. Extensively drug resistant TB (XDRTB) was seen in 4.3% of MDR-TB cases. Any OFX resistance was seen in 10.4% of NSP, 13.9% of PT and 29% of PT MDR-TB patients. The HIV status of the patient had no impact on drug resistance levels. RMP resistance was present in 2.6% of new and 15.1% of previously treated patients in Tamil Nadu. Rates of OFX resistance were high among NSP and PT patients, especially among those with MDR-TB, a matter of concern for development of new treatment regimens for TB.     

Has introduction of rapid drug susceptibility testing at diagnosis impacted treatment outcomes among previously treated tuberculosis patients in Gujarat,India?

Background

Revised National TB Control Programme (RNTCP) in India recommends that all previously-treated TB (PT) patients are offered drug susceptibility testing (DST) at diagnosis, using rapid diagnostics and screened out for rifampicin resistance before being treated with standardized, eight-month, retreatment regimen. This is intended to improve the early diagnosis of rifampicin resistance and its appropriate management and improve the treatment outcomes among the rest of the patients. In this state-wide study from Gujarat, India, we assess proportion of PT patients underwent rapid DST at diagnosis and the impact of this intervention on their treatment outcomes.

Methods

This is a retrospective cohort study involving review of electronic patient-records maintained routinely under RNTCP. All PT patients registered for treatment in Gujarat during January-June 2013 were included. Information on DST and treatment outcomes were extracted from ''presumptive DR-TB patient register'' and TB treatment register respectively. We performed a multivariate analysis to assess if getting tested is independently associated with unfavourable outcomes (death, loss-to-follow-up, failure, transfer out).

Results

Of 5,829 PT patients, 5306(91%) were tested for drug susceptibility with rapid diagnostics. Overall, 71% (4,113) TB patients were successfully treated - 72% among tested versus 60% among non-tested. Patients who did not get tested at diagnosis had a 34% higher risk of unsuccessful outcomes as compared to those who got tested (aRR - 1.34; 95% CI 1.20-1.50) after adjusting for age, sex, HIV status and type of TB. Unfavourable outcomes (particularly failure and switched to category IV) were higher among INH-resistant patients (39%) as compared to INH-sensitive (29%).

Conclusion

Offering DST at diagnosis improved the treatment outcomes among PT patients. However, even among tested, treatment outcomes remained suboptimal and were related to INH resistance and high loss-to-follow-up. These need to be addressed urgently for further progress.