Monday, 27 April 2015

MRI Helps Depict Clinically Undetectable Risk Factors in Advanced Stage Retinoblastomas

If diagnosed early, retinoblastoma is a highly curable cancer. Conservative treatment options have significantly improved in the last decades. The main aims in the management of retinoblastoma are maintaining the eye and reducing the systemic toxicity. A combination of local treatments, systemic and/or peri-ocular chemotherapy, external beam radiation, and enucleation have been used to successfully treat the tumour.


Our data [http://neu.sagepub.com/content/28/1/53.full] confirm the usefulness of high-resolution brain and orbit MRI in combination with clinical examinations in detecting possible risk factors for metastasis in advanced stages retinoblastomas leading to correct “customized” treatments. In particular, pre-laminar optic nerve and scleral infiltration suspected at MRI were strongly associated with the histology findings, and overall choroid provided good performances in sensitivity, NPV and accuracy. LEICR sign could be included in optic nerve evaluation at MRI, and AASE has been confirmed as a valuable additional sign alerting an increasing risk of metastasis.

Friday, 20 March 2015

Percutaneous Injection of Radiopaque Gelified Ethanol for the Treatment of Lumbar and Cervical Intervertebral Disk Herniations

Experience and Clinical Outcome in 80 Patients


BACKGROUND AND PURPOSE: Chemonucleolysis represents a minimally invasive percutaneous technique characterized by an intradiskal injection of materials under fluoroscopic or CT guidance. Recently, a substance based on radiopaque gelified ethanol has been introduced. The purpose of this study was to describe the indications, procedure, safety, and efficacy of radiopaque gelified ethanol in the percutaneous treatment of cervical and lumbar disk herniations.
MATERIALS AND METHODS: Between September 2010 and August 2013, 80 patients (32 women and 48 men; age range, 18–75 years) were treated for 107 lumbar disk herniations (L2–L3, n = 1; L3–L4, n = 15; L4–L5, n = 53; and L5–S1, n = 38) and 9 cervical disk herniations (C4–C5, n = 2; C5–C6, n = 2; C6–C7, n = 3; and C7–D1, n = 2) by percutaneous intradiskal injection of radiopaque gelified ethanol under fluoroscopic guidance. Thirty-six patients underwent a simultaneous treatment of 2 disk herniations. Patient symptoms were resistant to conservative therapy, with little or no pain relief after 4–6 weeks of physical therapy and drugs. All patients were evaluated by the Visual Analog Scale and the Oswestry Disability Index.
RESULTS: Sixty-two of 73 (85%) patients with lumbar disk herniations and 6/7 (83%) patients with cervical disk herniations obtained significant symptom improvement, with a Visual Analog Scale reduction of at least 4 points and an Oswestry Disability Index reduction of at least 40%. Leakage of radiopaque gelified ethanol in the surrounding tissues occurred in 19 patients, however without any clinical side effects.
CONCLUSIONS: In our experience, percutaneous intradiskal injection of radiopaque gelified ethanol is safe and effective in reducing the period of recovery from disabling symptoms.

Abbreviations

CDH
 
cervical disk herniation
 
LDH
 
lumbar disk herniation
 
ODI
Oswestry Disability Index
 
RGE
 
radiopaque gelified ethanol
 
VAS
Visual Analog Scale

Saturday, 14 March 2015

Cerebral Circulation Time is Prolonged and Not Correlated with EDSS in Multiple Sclerosis Patients

Literature has suggested that changes in brain flow circulation occur in patients with multiple sclerosis

In this study, digital subtraction angiography (DSA) was used to measure the absolute CCT value in MS patients and to correlate its value to age at disease onset and duration, and to expand disability status scale (EDSS). 

DSA assessment was performed on eighty MS patients and on a control group of forty-four age-matched patients. CCT in MS and control groups was calculated by analyzing the angiographic images. Lesion and brain volumes were calculated in a representative group of MS patients. Statistical correlations among CCT and disease duration, age at disease onset, lesion load, brain volumes and EDSS were considered. 

A significant difference between CCT in MS patients (mean = 4.9s; sd = 1.27s) and control group (mean = 2.8s; sd = 0.51s) was demonstrated. No significant statistical correlation was found between CCT and the other parameters in all MS patients. 

Significantly increased CCT value in MS patients suggests the presence of microvascular dysfunctions, which do not depend on clinical and MRI findings. Hemodynamic changes may not be exclusively the result of a late chronic inflammatory process.



Figure. DSA examination: antero-posterior lateral views of color-coded right carotid artery of control (panels a, b) and MS patients (panels c, d).



Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism

In about 50% of sporadic cases of retinoblastoma, no constitutive RB1 mutations are detected by conventional methods. 

However, recent research suggests that, at least in some of these cases, there is somatic mosaicism with respect to RB1 normal and mutant alleles. The increased availability of next generation sequencing improves our ability to detect the exact percentage of patients with mosaicism. Using this technology, we re-tested a series of 40 patients with sporadic retinoblastoma: 10 of them had been previously classified as constitutional heterozygotes, whereas in 30 no RB1 mutations had been found in lymphocytes. In 3 of these 30 patients, we have now identified low-level mosaic variants, varying in frequency between 8 and 24%. In 7 out of the 10 cases previously classified as heterozygous from testing blood cells, we were able to test additional tissues (ocular tissues, urine and/or oral mucosa): in three of them, next generation sequencing has revealed mosaicism.

Present results thus confirm that a significant fraction (6/40; 15%) of sporadic retinoblastoma cases are due to postzygotic events and that deep sequencing is an efficient method to unambiguously distinguish mosaics. Re-testing of retinoblastoma patients through next generation sequencing can thus provide new information that may have important implications with respect to genetic counseling and family care.

link to the paper

Monday, 9 March 2015

Lifelong accumulation of amyloid in neurons may contribute to Alzheimer's Disease


A research team at the Cognitive Neurology and Alzheimer’s Disease Center  - Northwestern University, Illinois, USA, found that the protein amyloid - a hallmark of this disease - begins to accumulate in the neurons of the brain since the age of 20 [see more here ]. Scientists believe that this is the first time that such changes were observed in the human brain of individuals so young. Prof. Changiz Gheula said:



Discovering that amyloid begins to accumulate so early in life is unprecedented. This is very significant. We know that amyloid, when present for long periods of time, is bad for you.

For the study, brains of deceased people in the age range from 20 to 95 were considered. Specifically, the sample included twenty-one people with Alzheimer's disease aged between 60 and 95, sixteen people aged between 70 and 79 without dementia, and thirteen "normal" people aged between 20 and 66 years.   

The findings are published in the journal Brain [download the pdf]

Wednesday, 14 January 2015

MULTICOLLINEARITY IN NONLINEAR MODELS

Multicollinearity is caused by the presence of linear relationship between the regressors. When the regressors are not orthogonal and become almost perfectly related, estimates of the individual regression coefficients may become unstable. Moreover, the inferences based on the model may tend to be misleading [1]. The effects, diagnostics and handling of multicollinearity in linear models have been discussed here.


1. Nonlinear model
Nonlinear regression is characterized by the fact that the prediction equation depends non linearly on one or more unknown parameters [2]. The basic nonlinear model has the form :

            1)             y = f(X, b)+e

where f(.) is a nonlinear (in the parameters b) differentiable function, f: Rn ® Rmy is the dependent variable (y Î Rm), X is a set of exogenous variables (X Î Rn), b represents the nonlinear parameter estimates to be computed (e.g. they can take the form of power or trigonometric or exponential or of any other nonlinear function) and e y - f(X, brepresents the vector of identically and independently distributed error terms (uncorrelated with the conditional mean function for all the observations: E[ei|f(Xi,b)] = 0 ). 

The objective function may be the usual sum-of-squares error in the form: 

            2) SSE = (1/2)×e×e  

to be minimized with respect to the vector of parameters b.

An analytical solution is not achievable because of the non linearity of the error function, therefore iterative methods are adopted for the parameter estimation, like the Gauss-Newton algorithm, Gradient descent algorithm,  Levenberg-Marquardt algorithm. 

Basically, the process of parameter adaptation at each step "i" returns: b(i) = b(i-1) Db(i-1)

Unlike the linear case, the hyper-plane defined by the error function is not always convex. The convergence of the algorithm may be slowed down by the transition across saddle-points and flat areas on the hyper-plane. Moreover, the algorithm may run into local minimum where it would remain [3].  




2. Does multicollinearity have a hold on nonlinear models too?
 
If the increase Db(i-1) is small the solution for those algorithms can be obtained [4from the first order Taylor series approximation of the error function SSE:

            3) SSE(b(i)) = SSE(b(i-1)) + Z×(Db(i-1))

where the elements of the matrix Z are the derivatives  

            4) Zij = {ei/bj}

Therefore, at step "i" the algorithm search to minimize the updated error function 3) with respect to the new value of bb(i)

            5) b(i) = b(i-1) – (Z×Z)-1×Z×SSE(b(i-1))

Under this form, the adaptive searching process recalls the pseudolinear regression (PLR)  (also called approximate maximum likelihood or extended least squares method) [5-7] which is computationally less cumbersome than the prediction error method [8]. 

This is not surprising, since the Taylor expansion at the first-order produces a linear approximation. 

In general, the elements of the Hessian matrix (H) for a sum-of-squares error function as in equation 2) are 

            6) Hij = {2SSE/bibj= {(e/bi)×e/bj) + e×(2e/bibj)}

H can then be approximated by the matrix Z×Z:

            7) (Z×Z)ij = {(e/bi)×e/bj)}

by discarding the term e×(2e/bibj) of the equation 6). 

This means that the minimization procedure of equation 5) calls for the Hessian matrix that multiplied by the gradient of the error function (ÑSSE = Z) yields the Newton step (or Newton direction):

8) b(i) = b(i-1) - H-1×ÑSSE

For finite data sets the solution driven by the 8) is exact only for linear problems. Instead, for nonlinear structures the Newton direction approaches the global minimum asymptotically (i.e. for infinite data sets). Therefore, for finite samples the Hessian should be estimated and updated at each step.  

The issue now is: independently of the sample size, the algorithm of pseudolinear regression implies the inversion of the Hessian matrix (i.e. of its approximated form Z×Z). 

Thus, the columns of (Z×Z)-1 must be linearly independent so as to make (Z×Z)-1 invertible. 

As a consequence, the issue of multicollinearity comes up in the nonlinear models during the iterative procedures of optimization



Understanding Anaerobic Threshold (VT2) and VO2 Max in Endurance Training

  Introduction: The Science Behind Ventilatory Thresholds Every endurance athlete, whether a long-distance runner, cyclist, or swimmer, st...