Lasso regularization for left-censored Gaussian outcome and high-dimensional predictors

Background

Biological assays for the quantification of markers may suffer from a lack of sensitivity and thus from an analytical detection limit. This is the case of human immunodeficiency virus (HIV) viral load. Below this threshold the exact value is unknown and values are consequently left-censored. Statistical methods have been proposed to deal with left-censoring but few are adapted in the context of high-dimensional data.

Methods

We propose to reverse the Buckley-James least squares algorithm to handle left-censored data enhanced with a Lasso regularization to accommodate high-dimensional predictors. We present a Lasso-regularized Buckley-James least squares method with both non-parametric imputation using Kaplan-Meier and parametric imputation based on the Gaussian distribution, which is typically assumed for HIV viral load data after logarithmic transformation. Cross-validation for parameter-tuning is based on an appropriate loss function that takes into account the different contributions of censored and uncensored observations. We specify how these techniques can be easily implemented using available R packages. The Lasso-regularized Buckley-James least square method was compared to simple imputation strategies to predict the response to antiretroviral therapy measured by HIV viral load according to the HIV genotypic mutations. We used a dataset composed of several clinical trials and cohorts from the Forum for Collaborative HIV Research (HIV Med. 2008;7:27-40). The proposed methods were also assessed on simulated data mimicking the observed data.

Results

Approaches accounting for left-censoring outperformed simple imputation methods in a high-dimensional setting. The Gaussian Buckley-James method with cross-validation based on the appropriate loss function showed the lowest prediction error on simulated data and, using real data, the most valid results according to the current literature on HIV mutations.

Conclusions

The proposed approach deals with high-dimensional predictors and left-censored outcomes and has shown its interest for predicting HIV viral load according to HIV mutations.

     

Insulin stimulates cord blood erythroid progenitor growth: evidence for an aetiological role in neonatal polycythaemia

Polycythaemia in the neonate is a serious pathologic entity which occurs particularly in infants of diabetic mothers (IDM) and small-for-gestational age (SGA) infants. Both of these conditions are associated with fetal hyperinsulinaemia. Cultures of cord blood mononuclear cells from polycythaemic IDM showed increased growth of late erythroid progenitor colonies, compared to cord blood mononuclear cells from non-polycythaemic infants, reflecting a possible expansion of this progenitor population in the polycythaemic fetus. No changes were observed in early erythroid progenitor populations. Biosynthetic human insulin at physiological levels characteristic of IDM stimulated growth in culture of late erythroid progenitors in cord blood from premature, term and IDM infants. Three out of five polycythaemic infants had elevated cord blood plasma levels of insulin C-peptide at birth, whereas no infant with a haematocrit of less than 65% had high insulin C-peptide measurements. These data suggest that the polycythaemia noted in infants of diabetic mothers may be secondary, in large part, to a stimulatory effect on erythroid progenitor growth by the hyperinsulinaemic environment in which they develop in utero.     

Hypertension artérielle endocrine

Endocrine hypertension represents more than half of the causes of secondary hypertension. This entity encompasses several diseases including primary aldosteronism, paraganglioma/pheochromocytoma and Cushing's syndrome. The screening of endocrine hypertension should be performed in all the patients presenting with: (1) a resistant hypertension; (2) a severe hypertension; (3) the coexistence of hypertension with an adrenal adenoma, clinical or biological abnormalities. Clinical signs and symptoms, whenever present, lack specificity, especially for primary aldosteronism where hypertension is usually the unique symptom. Screening is performed by the measurement of several hormones and by a tomodensitometry to study the morphology of the adrenals: the presence of a solitary or multiples adenomas, or hyperplasia. Pheochromocytoma and Cushing's syndrome are very uncommon and should be referred to specialized centres. Primary aldosteronism is a frequent cause of secondary hypertension. Once the diagnosis is obtained, it is essential to differentiate whether it is a surgically correctable form or not. The patients with a bilateral adrenal hyperplasia can be managed effectively by mineralocorticoids receptor antagonist. The adrenalectomy will cure or improve hypertension for the majority of the patients with a lateralized secretion of aldosterone. The diagnosis and the treatment of these disorders can be challenging. However, the diagnosis of endocrine hypertension allows diagnosing surgical correctable form of hypertension, which is not possible in essential hypertension.     

Occupational exposure to indium: what does biomonitoring tell us?

Background

The industrial uses of indium, a rare metal with no known physiological role in humans, have increased dramatically over the past 15 years.The results of animal toxicity studies showing pulmonary and systemic effects as well as some reports in workers have created a growing concern about the possible occurrence of toxic effects in exposed workers. Validated biomarkers to assess exposure to indium are not available.

Objectives

This work aimed at investigating the kinetics of indium in urine (In-U) and plasma (In-Pl) in workers manufacturing In ingots and mainly exposed to hardly water-soluble In compounds. All nine workers from the In department of a large metallurgical concern participated in the study as well as 5 retired workers and 20 controls.

Methods

Personal breathing zone air was collected throughout the work shift on Monday and Friday. Blood and urine samples were collected, before and after the shift, on the same day as the air sampling and on preshift the next Monday after a non-working week-end. Moreover, rats were given either InCl₃ by intraperitoneal injection or In₂O₃ by pharyngeal aspiration, In was followed in plasma during 120 days and measured in tissues 120 days after exposure.

Results

Higher In-Pl and In-U concentrations were found in both current (range 0.32–12.61 μg/L plasma; 0.22–3.50 μg/g creat) and former (0.03–4.38 μg/L plasma; 0.02–0.69 μg/g creat) workers compared with controls (<0.03 μg/L plasma; <0.02 μg/g creat). Both biological parameters were highly correlated but no correlation was found between In-air (10–1030 μg/m³) and In-Pl or In-U. Normalizing In-U by the urinary creatinine concentration reduced the inter- (from 90% to 70%) and intra-individual variability (from 54% to 35%). In-Pl remained remarkably stable along the working week (inter- and intra-individual variability: 89% and 10%, respectively). Neither In-U nor In-Pl significantly increased during the day or the week. A week-end without occupational exposure was not sufficient to reach the background In-Pl and In-U levels measured in controls. The results of the experimental investigations confirmed the hypothesis that inhalation of hardly soluble In compounds may cause accumulation of In in the body leading to a prolonged “endogenous exposure” from both a lung depot of “insoluble” particles that are progressively absorbed and from a retention depot in other internal organs.

Conclusion

This study shows that in workers exposed to hardly soluble In compounds, In-U and In-Pl are very sensitive to detect exposure and mainly reflect long-term exposure. In-Pl levels are particularly stable for a given individual. In-U might be more influenced than In-Pl by recent exposure. Both parameters remained high years after withdrawal from exposure, indicating a possible endogenous exposure and a prolonged risk of pulmonary and systemic diseases even after work exposure has ceased.     

Short, discontinuous exposure to butyrate effectively sensitizes latently EBV-infected lymphoma cells to nucleoside analogue antiviral agents

Antiviral drugs alone have been unsuccessful in the treatment of Epstein-Barr virus (EBV)-associated malignancies because the virus maintains a latent state of replication in these tumors. In recent years, novel therapeutic approaches are being investigated wherein lytic replication of the virus is induced prior to the use of cytotoxic antiviral drugs. The choice of suitable agents to induce lytic replication has been a critical step in this novel approach. We have previously demonstrated that butyrate derivatives induce a lytic pattern of EBV gene expression in patient-derived EBV-positive lymphoblastoid cell lines and, together with nucleoside analogue ganciclovir, effectively reduce or eliminate tumor growth in humans. Butyrate has drawbacks as a therapeutic agent, however, as constant intravenous infusion is required to achieve detectable plasma levels of this drug. In this study, we investigated whether discontinuous exposure to butyrate is capable of initiating lytic phase gene expression and thymidine kinase induction, and sensitizing EBV-positive lymphoma cells to ganciclovir-mediated cell growth arrest and apoptosis. We demonstrate that multiple daily 6-h exposures of the EBV-positive Burkitt's lymphoma cell line P3HR1 to butyrate induced sustained expression of the EBV lytic phase protein BMRF. Viral thymidine kinase was also induced by intermittent exposure, although to a lower level than with continuous exposure treatment. However, discontinuous exposure to butyrate in combination with ganciclovir induced a similar level of tumor cell growth inhibition as did continuous treatment, as measured by serial enumeration of viable cells, MTT cell proliferation assays and measurement of cellular DNA content. We further demonstrated that those cells which survived initial exposure to butyrate plus ganciclovir remained susceptible to further cycles of combination treatment. These findings suggests that continuous infusion of butyrate may not be necessary for maintaining viral thymidine kinase gene expression and sensitization to antiviral agents in EBV-associated tumors, and that therapeutic regimens which employ more convenient, discontinuous exposure to butyrate may also be effective clinically.     

Proposal of an algorithm for diagnosis and treatment of neonatal seizures in developing countries

Seizures in the neonatal period are common. They can be caused by a variety of conditions, ranging from benign, self-limited illnesses to severe, life-threatening disorders. They are often the first sign of neurologic dysfunction in neonates, and may be used as one factor in considering long-term prognosis. An important mission of the International League Against Epilepsy (ILAE) is to improve the care of patients with epilepsy. Most recently, as part of the Global Campaign against Epilepsy, ILAE, in conjunction with the World Health Organization (WHO), established a new initiative to create clinical guidelines and diagnostic and management algorithms for the care of patients with seizures that can be applied worldwide, including in developing countries with limited or varied medical resources. Created by an international panel of experts in seizure management and guideline development, this document proposes guidelines for the diagnosis and management of the most common and important conditions that cause seizures in the neonatal period. The publication of these clinical pathways for neonatal seizures will be followed by a period of field testing and comment by WHO clinicians and officials before finalization.     

Infantile spasms as an epileptic feature of DEND syndrome associated with an activating mutation in the potassium adenosine triphosphate (ATP) channel, Kir6.2

Activating mutations in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium (KATP) channel is a cause of neonatal diabetes associated with various neurological disorders that include developmental delay, epilepsy, and neonatal diabetes (known together as DEND syndrome). This article reports a girl who developed infantile spasms and early onset diabetes mellitus at the age of 3 months and revealed DEND syndrome with a heterozygous activating mutation in Kir6.2. Infantile spasms with hypsarrhythmia on the electroencephalogram were severe and refractory to steroids. Steroids combined with oral sulfonylurea, a drug that closes the ATP-sensitive potassium channel by an independent mechanism, allowed partial and transitory control of the epilepsy. However, the child still exhibited severe encephalopathy and died of aspiration pneumonia. The role of oral sulfonylurea as an anticonvulsant in DEND syndrome associated with Kir6.2 mutation is discussed.     

Differential contribution of GABAergic and glycinergic components to inhibitory synaptic transmission in lamina II and laminae III-IV of the young rat spinal cord

Using whole-cell patch-clamp recordings from spinal cord slices of young (10-15 days old) rats, we have characterized and compared the properties of inhibitory synaptic transmission in lamina II and laminae III-IV of the dorsal horn, which are involved in the processing of nociceptive and non-nociceptive sensory information, respectively. All (100%) of laminae III-IV neurons, but only 55% of lamina II neurons, received both gamma-aminobutyric acid (GABA)ergic and glycinergic inputs. The remaining 45% of lamina II neurons received only GABAergic synapses. Neurons receiving only glycinergic synapses were never observed. Among the 55% of lamina II neurons receiving both GABAergic and glycinergic inputs, all displayed a small proportion (approximately 10%) of mixed miniature inhibitory postsynaptic currents (mIPSCs), indicating the presence of a functional GABA/glycine co-transmission at a subset of synapses. Such a co-transmission was never observed in laminae III-IV neurons. The presence of mixed mIPSCs and the differences in decay kinetics of GABAA-type receptor mIPSCs between lamina II and laminae III-IV were due to the endogenous tonic production of 3alpha5alpha-reduced steroids (3alpha5alpha-RS) in lamina II. Stimulation of the local production of 3alpha5alpha-RS was possible in laminae III-IV after incubation of slices with progesterone, subcutaneous injection of progesterone or induction of a peripheral inflammation. This led to the prolongation of GABAergic mIPSCs, but failed to induce the appearance of mixed mIPSCs in laminae III-IV. Our results indicate that, compared with lamina II, inhibitory synaptic transmission in laminae III-IV is characterized by a dominant role of glycinergic inhibition and the absence of a functional GABA/glycine co-transmission.     

Contrasting effects of basic fibroblast growth factor and epidermal growth factor on mouse neonatal olfactory mucosa cells

Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) affect proliferation and survival of many cell types, but their role in the maintenance of olfactory mucosa cells remains unclear. In the neonatal mouse olfactory mucosa, cell proliferation mainly occurs in the neuroepithelium and, to a lesser extent, in the lamina propria. To establish whether bFGF and EGF affect proliferation and/or survival of these cells, we isolated olfactory mucosa cells from the neonatal mouse and cultured them as free-floating spheres under bFGF or EGF stimulation. Our data demonstrate that bFGF is a mitogen for the rapidly dividing cells (olfactory neuronal precursors and olfactory ensheathing cells), and also a survival factor for both slowly and rapidly dividing cells of the olfactory mucosa. In contrast, EGF appears to be primarily a survival factor for both the olfactory stem and precursor cells.