Density-based clustering of static and dynamic functional MRI connectivity features obtained from subjects with cognitive impairment.

Various machine-learning classification techniques have been employed previously to classify brain states in healthy and disease populations using functional magnetic resonance imaging (fMRI). These methods generally use supervised classifiers that are sensitive to outliers and require labeling of training data to generate a predictive model. Density-based clustering, which overcomes these issues, is a popular unsupervised learning approach whose utility for high-dimensional neuroimaging data has not been previously evaluated. Its advantages include insensitivity to outliers and ability to work with unlabeled data. Unlike the popular k-means clustering, the number of clusters need not be specified. In this study, we compare the performance of two popular density-based clustering methods, DBSCAN and OPTICS, in accurately identifying individuals with three stages of cognitive impairment, including Alzheimer's disease. We used static and dynamic functional connectivity features for clustering, which captures the strength and temporal variation of brain connectivity respectively. To assess the robustness of clustering to noise/outliers, we propose a novel method called recursive-clustering using additive-noise (R-CLAN). Results demonstrated that both clustering algorithms were effective, although OPTICS with dynamic connectivity features outperformed in terms of cluster purity (95.46%) and robustness to noise/outliers. This study demonstrates that density-based clustering can accurately and robustly identify diagnostic classes in an unsupervised way using brain connectivity.

A Novel Technique for Fixation of Non-union Unicondylar Hoffa's Fracture: A Case Report.

Hoffa fractures are rare and difficult fractures to manage. Hoffa fracture involves a coronal plane fracture of posterior femoral condyle. Non-union in Hoffa fracture is further difficult to manage. The surgical management for such nonunion includes open reduction with recon/LCP plate or screw fixation with bone grafting. The problem with plates is the difficulty in contouring the plates according to the shape of posterior femoral condyles. We describe a new technique with 2 L shaped neutralisation plates placed in a circular fashion. This technique provides a more rigid construct and gives better holding strength of screws in Hoffa fragment. This enhances union and mobilisation can be started early.

Risk factors associated with default among retreatment tuberculosis patients on DOTS in Paschim Medinipur district (West Bengal).

BACKGROUND: In India in 2010, 14.1% of retreatment of TB patients' treatment outcome was 'default'. Since 2002, in Paschim Midnapur District (West Bengal), it has been around 15-20%. OBJECTIVES: To determine the timing, characteristics and risk factors associated with default among retreatment TB patients on DOTS. METHODOLOGY: It was a case control study, conducted in six TB units (TU) of Paschim Midnapur District, which were selected by simple random sampling. Data was collected from treatment records of TUs/DTC. Data was also collected through interviews of the patients using the same pre-tested semi-structured questionnaire from 87 defaulters and 86 consecutively registered non-defaulters registered in first quarter, 2009 to second quarter, 2010. RESULTS: Median duration of treatment taken before default was 121 days (inter-quartile range of 64-176 days). Median number of doses of treatment taken before default was 36 (inter -quartile range of 26-63 doses). No retrieval action was documented in 57.5% cases. Retrieval was done between 0-7 days of missed doses in 29.9% cases. Multiple logistic regression analysis indicated the following important risk factors for default at 95% confidence interval: male-sex limit: [aOR 3.957 (1.162-13.469)], alcoholic inebriation[ aOR6.076 (2.088-17.675)], distance from DOT centre [aOR 4.066 (1.675-9.872)], number of missed doses during treatment [aOR 1.849 (1.282-2.669)] and no initial home visit [aOR 10.607 (2.286 -49.221)]. CONCLUSION: In Paschim Midnapur district, default of retreatment TB occurs mostly after a few doses in continuation phase. Initial home visit, patient provider meeting, retrieval action, community-based treatment as per RNTCP guidelines are required to uplift the programme.

microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600 000 new cases diagnosed each year. Understanding the molecular pathways that lead to HNSCC is crucial to identify new targets for anti-cancer drug development. Protein kinase Cɛ (PKCɛ) is elevated in HNSCC and regulates the activation of Akt, Stat3 and Rho GTPases. To date, the molecular mechanism of PKCɛ dysregulation in HNSCC remains to be elucidated. In silico analysis identified three putative microRNA-107 (miR-107) binding sites in the 3'-untranslated region (UTR) of PKCɛ. An inverse relationship was revealed between miR-107 and PKCɛ in HNSCC cell lines. Delivery of miR-107 reduced PKCɛ levels in SCC15, SCC25 and CAL27, three HNSCC cell lines with high PKCɛ and low miR-107. The activity of a luciferase reporter construct containing the 3'-UTR of PKCɛ was downregulated by miR-107 and mutations in the three cognate miR-107 binding sites completely ablated the regulation by miR-107. Treatment with miR-107 significantly blocked cell proliferation, DNA replication, colony formation and invasion in SCC25 and CAL27 cells. Ectopic expression of miR-resistant PKCɛ was sufficient to partially rescue the loss-of-function phenotype in miR-107-overexpressing SCC25 cells. Tumor growth in nude mice was retarded by 93±7% in CAL27/miR-107 cells compared with CAL27/miR-control cells. Last, human primary HNSCC tumors with elevated PKCɛ had reduced miR-107 expression. Our results demonstrate that PKCɛ is directly regulated by miR-107 and, moreover, suggest that miR-107 may be a potential anti-cancer therapeutic for HNSCC.

A note on fractal dimensions of biomedical waveforms.

In this paper, we study performance of Katz method of computing fractal dimension of waveforms, and its estimation accuracy is compared with Higuchi's method. The study is performed on four synthetic parametric fractal waveforms for which true fractal dimensions can be calculated, and real sleep electroencephalogram. The dependence of Katz's fractal dimension on amplitude, frequency and sampling frequency of waveforms is noted. Even though the Higuchi's method has given more accurate estimation of fractal dimensions, the study suggests that the results of Katz's based fractal dimension analysis of biomedical waveforms have to be carefully interpreted.

Complexity analysis of EEG in patients with schizophrenia using fractal dimension.

We computed Higuchi's fractal dimension (FD) of resting, eyes closed EEG recorded from 30 scalp locations in 18 male neuroleptic-naïve, recent-onset schizophrenia (NRS) subjects and 15 male healthy control (HC) subjects, who were group-matched for age. Schizophrenia patients showed a diffuse reduction of FD except in the bilateral temporal and occipital regions, with the reduction being most prominent bifrontally. The positive symptom (PS) schizophrenia subjects showed FD values similar to or even higher than HC in the bilateral temporo-occipital regions, along with a co-existent bifrontal FD reduction as noted in the overall sample of NRS. In contrast, this increase in FD values in the bilateral temporo-occipital region was absent in the negative symptom (NS) subgroup. The regional differences in complexity suggested by these findings may reflect the aberrant brain dynamics underlying the pathophysiology of schizophrenia and its symptom dimensions. Higuchi's method of measuring FD directly in the time domain provides an alternative for the more computationally intensive nonlinear methods of estimating EEG complexity.

TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL.

Transforming growth factor-beta (TGF-beta) potently induces apoptosis in Burkitt's lymphoma (BL) cell lines and in explanted primary human B lymphocytes. The physiological relevance and mechanism of TGF-beta-mediated apoptosis induction in these cells remains to be determined. Here we demonstrate the requirement for TGF-beta-mediated regulation of BIK and BCL-X(L) to activate an intrinsic apoptotic pathway in centroblastic BL cells. TGF-beta directly induced transcription of BIK and a consensus Smad-binding element identified in the BIK promoter recruits TGF-beta-activated Smad transcription factor complexes in vivo. TGF-beta also transcriptionally repressed expression of the apoptosis inhibitor BCL-X(L). Inhibition of BCL-X(L) sensitised BL cells to TGF-beta-induced apoptosis whereas overexpression of BCL-X(L) or suppression of BIK by shRNA, diminished TGF-beta-induced apoptosis. BIK and BCL-X(L) were also identified as TGF-beta target genes in purified normal human centroblast B cells and immunohistochemical analyses of tonsil tissue revealed widespread TGF-beta receptor-regulated Smad activation and a focal pattern of BIK expression. Furthermore, using a selective inhibitor of the TGF-beta receptor we provide evidence that autocrine TGF-beta signalling through ALK5 contributes to the default apoptotic programme in normal human centroblasts undergoing spontaneous apoptosis. Our data suggests that TGF-beta may act as a physiological mediator of human germinal centre homoeostasis by regulation of BIK and BCL-X(L).

Cross-sectional study of consumption, compliance and awareness about antibiotic utilisation amongst the urban community in Kolkata.

A cross-sectional survey was conducted upon 500 respondents, comprising of 250 adults and 250 children who did consume antibiotics in the previous three months. Data were analysed to determine the patterns of utilisation, compliance and awareness regarding antibiotic medication amongst a selected urban population at Kolkata. Antibiotic consumption without prescription was evident amongst 41.2% of adults in comparison to that of 8.4% in children (P < 0.01). Compliance to daily dosage was observed in 40.8% of adults in comparison to 82.8% in children (P < 0.01). Awareness pattern regarding antibiotics were reported to have been more in the children group (16.4%) while compared to the adults (8%). The knowledge regarding antibiotic resistance remained more or less similar in both the groups. The study concludes that high over the counter (OTC) sale and inadequate compliance to antibitotic medication needs further intervention approach towards information, education and communication (IEC) to all concerned.

Ciprofloxacin reduces the stimulation of prostaglandin E(2) output by interleukin-1beta in human tendon-derived cells.

OBJECTIVE: Fluoroquinolone antibiotics such as ciprofloxacin can induce tendon pathology and have various effects on tendon-derived cells in culture. We are investigating whether ciprofloxacin modifies signalling responses in tendon cells. METHODS: Human Achilles tendon-derived cells were preincubated with or without ciprofloxacin (50 mug/ml) and were then challenged with interleukin-1beta (IL-1beta, 1 ng/ml) for up to 48 h. Prostaglandin E2 (PGE2) output was assayed by ELISA. The expression of cyclooxygenase-2 (COX-2) was examined by Western blotting. RESULTS: IL-1beta stimulated a substantial and prolonged increase in the output of PGE2. Preincubation with ciprofloxacin reduced IL-1beta-induced PGE2 output at all times tested; the reduction at 48 h was 69% (99% confidence interval 59-79%; 15 experiments). Norfloxacin and ofloxacin also reduced PGE2 output. However, ciprofloxacin did not affect the induction of COX-2 by IL-1beta, measured at 4 or 48 h. CONCLUSIONS: Ciprofloxacin reduces IL-1beta-induced PGE2 output in tendon-derived cells. The reduction in PGE2 output could modulate various cellular activities of IL-1beta, and may be implicated in fluoroquinolone-induced tendinopathy.

A dynamic nonlinear time domain model for reconstruction and compression of cardiovascular signals with application to telemedicine.

A new nonlinear time domain model is proposed in this paper for signals of cardiovascular origin. An equation of the dynamic nonlinear model has been obtained by considering a masking function, which is modulated by a harmonic series with the baseline drift incorporated into the model. Signal reconstruction using model parameters has established the effectiveness of the model for signal compression. Improvement has been effected by using neural networks for reducing the time for optimizing the initial parameters. An improved adaptive optimization step size algorithm has also been implemented. Results show that the technique is able to provide reasonable compression with low error between the original and reconstructed signals. One of the main advantages of the model is its potential of being used for compression of many different types of biosignals transmitted in parallel. Incorporation of the compression model into a telemedicine system has led to considerable saving in transmission time for patient data.

Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes.

Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirty-two patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P =.002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P =.003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P =.016), a lower duration of pretherapy platelet transfusions (P =.013), and higher pretherapy platelets (P =.003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed sideroblasts; and 2 had RA with excess blasts. By ITT analysis, 19% of patients (16 of 83) responded, and when only evaluable patients were analyzed, 31% (16 of 51) responded. It was concluded that thalidomide, as a single agent, is effective in improving cytopenias of some MDS patients, especially those who present without excess blasts. (Blood. 2001;98:958-965)

The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes.

Thirty patients with myelodysplastic syndromes (MDS) were treated with thalidomide at 100 mg/d p.o., increased as tolerated to 400 mg/d for 12 weeks. Levels of apoptosis, macrophage number, microvessel density (MVD), tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin 6 (IL-6), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined in the serum, bone marrow (BM) plasma and BM biopsies before and after therapy. Pretherapy biological characteristics of MDS patients were compared with similar studies performed in 11 normal volunteers. Ten patients demonstrated haematological improvement in the erythroid series, six becoming transfusion independent. Responders had a higher pretherapy platelet count (P < 0.048) and lower BM blasts (P < 0.013). Median time to response was 10 weeks, and four remain in remission beyond a year. Pretherapy MDS BMs showed higher MVD (P < 0.001) and TGF-beta (P < 0.03) and higher serum TNF-alpha (P < 0.008) compared with normal control subjects. After therapy, only BM TGF-beta decreased significantly (P < 0.002). Pretherapy haemoglobin was directly related to serum VEGF (P < 0.001) in responders and inversely related in non-responders (P < 0.05), suggesting the possibility that angiogenesis may be a primary pathology in the former and a consequence of anaemia-induced hypoxia in the latter. We conclude that thalidomide has important clinical and biological effects in at least a subset of MDS patients, but the precise mechanism of its action remains unknown and requires further study including a larger number of patients.

The clinical and biologic significance of abnormal lipid profiles in patients with myelodysplastic syndromes.

Serum lipid profiles were obtained in 108 patients with myelodysplastic syndrome (MDS) and compared to 28 healthy volunteers. Serum cholesterol and low-density and high-density lipoproteins (LDL and HDL) were found to be significantly lower in MDS patients than in normals (p = 0.0001, 0.0038 and 0.037, respectively). This difference was significant for all MDS categories. Serum cholesterol and HDL were negatively related to biopsy cellularity (p = 0.001 and 0.0001, respectively), and serum triglycerides were negatively related to labeling index (p = 0.0003). No differences were noted in the lipid profiles of MDS patients with normal versus abnormal karyotypes. However, low-risk MDS patients with abnormal karyotypes had significantly lower triglyceride levels compared with the high-risk patients (p = 0.027), as did low-risk patients with normal cytogenetics (p = 0.015). Serum HDL levels were significantly higher for the low-risk group with normal cytogenetics as well (p = 0.003). We conclude that serum cholesterol, LDL, and HDL are significantly reduced in MDS patients, probably indicating excessive intracellular lipid biosynthesis in the expanding clone. These relatively simple measurements could serve as important prognostic markers and reliable indicators of disease activity in individual patients. Prospective studies to determine their utility as independent variables that guide the need for active therapeutic intervention are warranted.

Nonlinear measures of heart rate time series: influence of posture and controlled breathing.

In this study, we investigated measures of nonlinear dynamics and chaos theory in regards to heart rate variability in 27 normal control subjects in supine and standing postures, and 14 subjects in spontaneous and controlled breathing conditions. We examined minimum embedding dimension (MED), largest Lyapunov exponent (LLE) and measures of nonlinearity (NL) of heart rate time series. MED quantifies the system's complexity, LLE predictability and NL, a measure of deviation from linear processes. There was a significant decrease in complexity (P < 0.00001), a decrease in predictability (P < 0.00001) and an increase in nonlinearity (P = 0.00001) during the change from supine to standing posture. Decrease in MED, and increases in NL score and LLE in standing posture appear to be partly due to an increase in sympathetic activity of the autonomous nervous system in standing posture. An improvement in predictability during controlled breathing appears to be due to the introduction of a periodic component.

A chaos-based model for low complexity predictive coding scheme for compression and transmission of electroencephalogram data.

A method for low complexity, low bit rate transmission of EEG (electroencephalogram) data, based on chaotic principles, is presented. The EEG data is assumed to be generated by a non-linear dynamical system of E dimensions. The E dynamical variables are reconstructed from the one-dimensional time series by the process of time-delay embedding. A model of the form X[n + 1] = F(X[n], X[n - 1], ... , X[n - p]) is fitted for the data in the E-dimensional space and this model is used as predictor in the predictive coding scheme for transmission. This model is able to give a reduction of nearly 50% of the dynamic range of the error signal to be transmitted, with a reduced complexity, when compared to the conventionally used linear prediction method. This implies that a reduced bit rate of transmission with a reduced complexity can be obtained. The effects of variation of model parameters on the complexity and bit rate are discussed.

Post-seizure EEG fractal dimension of first ECT predicts antidepressant response at two weeks.

BACKGROUND: Duration of seizure by itself is an insufficient criterion for a therapeutically adequate seizure in ECT. Therefore, measures of seizure EEG other than its duration need to be explored as indices of seizure adequacy and predictors of treatment response. We measured the EEG seizure using a geometrical method-fractal dimension (FD) and examined if this measure predicted remission. METHODS: Data from an efficacy study on melancholic depressives (n = 40) is used for the present exploration. They received thrice or once weekly ECTs, each schedule at two energy levels - high or low energy level. FD was computed for early-, mid- and post-seizure phases of the ictal EEG. Average of the two channels was used for analysis. RESULTS: Two-thirds of the patients (n = 25) were remitted at the end of 2 weeks. As expected, a significantly higher proportion of patients receiving thrice weekly ECT remitted than in patients receiving once weekly ECT. Smaller post-seizure FD at first ECT is the only variable which predicted remission status after six ECTs. Within the once weekly ECT group too, smaller post-seizure FD was associated with remission status. CONCLUSIONS: Post-seizure FD is proposed as a novel measure of seizure adequacy and predictor of treatment response. CLINICAL IMPLICATIONS: Seizure measures at first ECT may guide selection of ECT schedule to optimize ECT. LIMITATIONS: The study examined short term antidepressant effects only. The results may not be generalized to medication-resistant depressives.

EEG seizure in bilateral ECT is different between low and high stimulus doses.

Melancholic depressive patients referred for ECT were randomized to receive either low dose (n = 20) or high dose (n = 20) stimulus applied bifrontotemporally. The two stimulus groups were comparable on the clinical variables. The EEG seizure was recorded on two channels (right and left frontal), digitized, coded and analyzed offline without knowledge of ECT parameters. EEG seizure was of comparable duration in the two stimulus (high dose and low dose) groups. A new composite measure, Strength-Symmetry-Index (SSI), based on strength and symmetry of seizure EEG was computed using fractal geometry. The SSI of the early-seizure was higher in the high dose than in the low dose ECT group. In a stepwise, logistic regression model, this variable contributed to 65% with correct classification of high dose and low dose ECT seizures.

Strength Symmetry Index: a measure of seizure adequacy in ECT.

Seizure electroencephalography (EEG) was recorded from two channels--right (Rt) and left (Lt)--during bilateral electroconvulsive therapy (ECT) (n = 12) and unilateral ECT (n = 12). The EEG was also acquired into a microcomputer and was analyzed without knowledge of the clinical details. EEG recordings of both ECT procedures yielded seizures of comparable duration. The Strength Symmetry Index (SSI) was computed from the early- and midseizure phases using the fractal dimension of the EEG. The seizures of unilateral ECT were characterized by significantly smaller SSI in both phases. More unilateral than bilateral ECT seizures had a smaller than median SSI in both phases. The seizures also differed on other measures as reported in the literature. The findings indicate that SSI may be a potential measure of seizure adequacy that remains to be validated in future research.