Trimester-specific reference intervals for thyroid function parameters in pregnant Caucasian women using Roche platforms: a prospective study.

BACKGROUND: Standard thyroid function parameters reference intervals (RI) are unsuitable during pregnancy, potentially resulting in incongruous treatments that may cause adverse effects on pregnancy outcomes. We aimed at defining trimester-specific TSH, FT4 and FT3 RI, using samples longitudinally collected from healthy Caucasian women. MATERIALS AND METHODS: Blood samples from 150 healthy Caucasian women, who had a physiological gestation and a healthy newborn at term, were collected in each trimester and at around six months post-partum. They showed mild iodine deficiency. After excluding women with overt TSH abnormalities (> 10 mU/L) and/or TPO antibodies, data from 139 pregnant women were analyzed by means of widely used Roche platforms, and TSH, FT4 and FT3 trimester-specific RI were calculated. Post-partum data were available for 55 subjects. RESULTS: Serum TSH RI were 0.34-3.81 mU/L in the first trimester, and changed slightly to 0.68-4.07 U/L and 0.63-4.00 mU/L in the second and third trimester, respectively. Conversely, both FT4 and FT3 concentrations progressively decreased during pregnancy, the median values in the third trimester being 14.8% and 13.2% lower, respectively, than in the first trimester. Thyroid function parameters in the first trimester were similar to those measured after the end of pregnancy. CONCLUSIONS: This study calculates trimester-specific RI for thyroid function parameters in pregnancy, and proposes the reference limits that should be adopted when using Roche platforms in Caucasian women.

Female pattern hair loss: A comprehensive review.

Female pattern hair loss is a common form of hair loss in women that increases in incidence with age. The etiology is unknown with numerous factors identified that influence its onset. Female pattern hair loss may be viewed as a marker for an increased risk of cardiovascular and metabolic disease. New treatments include microneedling, low-level laser therapy, and autologous fat transfer. This article focuses on the pathophysiology, diagnosis, systemic associations, and current treatments for female pattern hair loss, which is the most common cause of alopecia in women.

Ultraviolet A-1 in Dermatological Diseases.

The exposure to ultraviolet radiations and visible light, or phototherapy, is a well-known therapeutic tool available for the treatment of many dermatological disorders. The continuos medical and technological progresses, of the last 50 years, have involved the field of phototherapy, which evolved from UVA and PUVA in its various forms, to the development of narrowband UVB (NB-UVB) and NB-UVB micro-focused phototherapies. Further advances in technology have now permitted the introduction of a new device emitting UVA-1 radiations.

Psycho-Neuro-Endocrine-Immunology: A Psychobiological Concept.

Psycho-Neuro-Endocrine-Immunology (P.N.E.I.) is a scientific field of study that investigates the link between bidirectional communications among the nervous system, the endocrine system, and the immune system and the correlations of this cross-talk with physical health. The P.N.E.I. innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary one. The key element of P.N.E.I. approach is represented by the concept of bidirectional cross-talk between the psychoneuroendocrine and immune systems. The Low Dose Medicine is one of the most promising approaches able to allow the researchers to design innovative therapeutic strategies for the treatment of skin diseases based on the rebalance of the immune response.

Classification of vitiligo: a challenging endeavor.

The classification of vitiligo is mandatory for clinical and research purposes. Although the etiology and pathobiology of vitiligo remain unknown, a working classification of vitiligo is imperative for the scientific community to communicate. The authors delineate herein their efforts for vitiligo classification utilizing clinical, genetic, pathobiological, epidemiological, and molecular characteristics of vitiligo. These different classification approaches may aid clinicians to identify the most suitable treatment for each individual vitiligo subject.

Metabolic syndrome in vitiligo.

Vitiligo is an acquired, depigmenting skin disease with still unclear, multifactorial etiopathogenesis. However, there is growing evidence that vitiligo affects not only the skin but it may also be connected with metabolic abnormalities, including glucose intolerance and lipid abnormalities, all of which confirms the systemic nature of the disease. Recently, it has been shown that melanocytes, especially those found in the adipose tissue, due to their ability to decrease inflammation and oxidative damage, are capable of preventing the metabolic syndrome. The article presents updated knowledge on potential metabolic disturbances in vitiligo.

Multidisciplinary approach to R&D in vitiligo, a neglected skin disease.

A global interest in therapies for neglected diseases is rising, but traditional biopharma research and development (R&D) process is prohibitively expensive to justify cost of their development. Vitiligo is a multifactorial orphan disease that affects at minimum 35 million people worldwide, yet no therapeutic solutions exist. The present authors describe a budget-minded pursuit of the new therapy development for vitiligo, which includes a multidiscipline collaboration and effective bridging between academic research, biobanking, and bioinformatics. The present authors anticipate that the present authors' "theoretically induced and empirically guided" discovery process will enable development of more leads, with a much greater probability of success and under tighter budgets compared with those of the biopharma company. Ultimately, the multidisciplinary approach described below facilitates the collaborative development of personalized treatments for different patient subpopulations in vitiligo and other neglected diseases.

Vitiligo road map.

Vitiligo is a depigmenting disorder stemming from melanocyte loss or dysfunction. It has a complex, multifaceted etiology. We constructed a "vitiligo road map," consisting of basic science, clinical, and treatment components, in order to better portray our current understanding of vitiligo pathogenesis and reflect upon novel biomarkers and therapeutic targets for future research. The melanocyte map elaborates on the molecular processes and intracellular signaling pathways initiated by various external autocrine/paracrine factors in representing normal melanocyte homeostatic functions modulating its viability, proliferation, differentiation, dendricity, migration, and melanogenic processes. This vitiligo map identifies known inducers/triggers of vitiligo onset and progression that cultivate a microenvironment for melanocyte disappearance, real or functional. This map describes the molecular mechanisms of currently utilized clinical and experimental treatments of vitiligo that facilitate repigmentation.

Treatments of vitiligo: what's new at the horizon.

Vitiligo is a manageable disease. However, current vitiligo treatments can be considered suboptimal as they do not guarantee high efficacy and cannot be standardized for most patients. Recently, combination therapies have been introduced in order to obtain better results and reduce risks in the management of the disease. Novel efficacious products are hereunder discussed to improve the therapeutic options for vitiligo patients.

Signaling cross-talk between IGF-binding protein-3 and transforming growth factor-(beta) in mesenchymal chondroprogenitor cell growth.

Cartilage formation is driven by mesenchymal chondroprogenitor cells (MCCs) that proliferate and differentiate into chondrocytes. The molecular mechanisms by which growth factors regulate MCC fate are not well defined. Insulin-like growth factor binding protein-3 (IGFBP-3) has intrinsic bioactivity that is independent of IGF binding. We previously reported that IGFBP-3 has IGF-independent antiproliferative and apoptotic effects in MCCs, and requires STAT-1 activation to mediate its apoptotic effect. Transforming growth factor-beta (TGF-beta) is a key chondroinductive growth factor. The objective of the study is to define the interactions between IGFBP-3 and TGF-beta in MCC growth and their intracellular signaling pathways. We used the RCJ3*1C5*18 mesenchymal chondrogenic cells that without biochemical or oncogenic transformation progress in culture from MCCs to differentiated chondrocytes. Cell proliferation was assessed in MCCs treated with IGFBP-3 or transfected with IGFBP-3, in the presence or absence of TGF-beta. To demonstrate that IGFBP-3 effects were IGF-independent an IGFBP-3 analog that lacks IGF binding was used (GGG-IGFBP-3). To determine the functional roles of the TGF-beta-mediated signaling and the STAT-1 pathway, cells were either stably transfected with a dominant negative TGF-beta type II receptor (MCC-DNTbetaRII) or treated with a STAT-1 morpholino antisense oligonucleotide. We found that in MCCs, TGF-beta antagonized the antiproliferative effect of IGFBP-3. IGFBP-3 increased the cyclin-dependent kinase inhibitor p21 expression and this effect was abolished by TGF-beta. Furthermore, TGF-beta inhibited STAT-1 phosphorylation induced by IGFBP-3. Similarly to TGF-beta, STAT-1 antisense oligonucleotide inhibited the IGFBP-3 antiproliferative action. Although TGF-beta in MCC-DNTbetaRII lacked Smad-mediated signaling, it persistently antagonized the IGFBP-3 antiproliferative action. However, TGF-beta even in MCC-DNTbetaRII cells induced ERK1/2 phosphorylation, and treatment with MEK inhibitor, UO126, inhibited the antagonistic effects of TGF-beta on IGFBP-3. Furthermore, UO126 blocked the TGF-beta inhibition of STAT-1 phosphorylation induced by IGFBP-3. Collectively, these results demonstrate cross-talk between the IGFBP-3-dependent STAT-1 signaling and the TGF-beta-dependent ERK pathway that regulates MCC proliferation.

Relationship between reduced BCL-2 expression in circulating mononuclear cells and early nephropathy in type 1 diabetes.

Microalbuminuria is the earliest clinical evidence of diabetic nephropathy, but the mechanisms linking hyperglycemia and kidney complications are not clear. The aim of this study was to evaluate whether enhanced oxidative stress in patients with microalbuminuria can contribute to diabetic nephropathy development through downregulation of the antiapoptotic gene Bcl-2 that promotes in turn a pro-inflammatory status. We studied 30 patients with type 1 diabetes (15 with and 15 without microalbuminuria) compared to 15 matched healthy controls. Plasma oxidant status, and expression of Bcl-2, activated NF-kB, inducible Nitric Oxide synthase (iNOS), and monocyte chemoattractant protein (MCP)-1 in circulating monocytes were evaluated at baseline and after 8-week oral vitamin E treatment (600 mg b.i.d.). Bcl-2 expression was significantly reduced in microalbuminuric diabetic patients as a consequence of increased oxidant burden secondary to persistent hyperglycemia. Bcl-2 down-regulation was associated with enhanced expression of NF-kB, iNOS and MCP-1, and showed a strong correlation with the albumin excretion rate. Low Bcl-2 expression and high inflammatory status were normalized by vitamin E both in vivo and in vitro. Our study showed that Bcl-2 down-regulation in diabetic patients with poor glycemic control results in the activation of the NF-kB pathway leading to the development of nephropathy. Vitamin E might provide a novel form of therapy for prevention of nephropathy in diabetic patients in which an acceptable glycemic control is difficult to achieve despite insulin therapy.

Vasopressin-induced antinociception: an investigation into its physiological and hormonal basis.

Systemically administered lysine-8-vasopressin (LVP; 16-128 micrograms/kg) was found to induce a potent and dose-dependent antinociceptive effect, as measured by the tail-flick test in the rat. This effect could be seen in the absence of any significant change in general activity, indicating that it was not due to sedation or general motor debilitation. The antinociceptive effect of LVP does not appear to be mediated by endogenous opiates or other pituitary hormones, as evidenced by: 1) the lack of antagonism by the opiate receptor blocker naloxone, 2) the lack of cross-tolerance with morphine, and 3) its persistence after hypophysectomy. Des-glycinamide-LVP, a vasopressin analog with no appreciable pressor or antidiuretic action, showed no antinociceptive activity (128 micrograms/kg), and des-amino-arginine-vasopressin, a vasopressin analog with minimal pressor activity but greatly enhanced antidiuretic activity, was also relatively ineffective (128 micrograms/kg). These results suggest that the antinociceptive activity of vasopressin may be related to receptor types similar to those mediating its pressor effects. Nevertheless, the antinociceptive action of vasopressin does not appear to be secondary to its pressor activity, since phenylephrine failed to induce an antinociceptive effect at a dosage that mimicked the pressor response to vasopressin. These results are in concert with a growing body of evidence suggesting that vasopressin may be one of several nonopiate peptides that play a role in the modulation of pain sensitivity.

P300 in schizophrenia: confirmation and statistical validation of temporal region deficit in P300 topography.

Comparison of normal and medicated schizophrenic groups on the auditory P300 component of the event-related potential confirmed our earlier finding of a left temporal deficit in P300 amplitude in schizophrenia. A difference in P300 topography between groups was evident in both color mapping and in grand-averaged waveforms, which was statistically validated by the presence of a group-by-scalp region interaction (p less than 0.05). The left temporal area in schizophrenics was denoted as the region of greatest deficit and of maximal statistical separation (p less than 0.05) relative to normals by t statistic mapping (SPM), Hotelling's T-squared "protected" contrasts of individual scalp regions, and the relative ratio of left scalp amplitudes to right scalp amplitudes. The left temporal scalp region yielding maximal group separation in the previous study also statistically separated the schizophrenic group from the normal group. This feature correctly differentiated 9 of 11 schizophrenics and 7 of 9 controls. These findings are compatible with other histological, metabolic, and electrophysiological studies suggesting temporal lobe abnormality in schizophrenia.

Leukoaraiosis in asymptomatic adult offspring of individuals with Alzheimer's disease.

The presence of white matter changes on magnetic resonance imaging (MRI), which has been referred to by Hachinski (1987) as leukoaraiosis, is frequently noted in elderly individuals in conditions ranging from health to frank dementia. This study involved the use of MRI to document cerebral structure if 41 healthy 50-60-year-old individuals, 28 of whom were offspring of Alzheimer's disease victims. On visual inspection of spin-echo images, 13 of the 28 offspring showed white matter lesions whereas all of the controls were free of leukoaraiosis. This statistically significant difference suggests that the presence of leukoaraiosis might be of importance in understanding changes in the white matter among populations at increased risk for Alzheimer's disease.

Correlations between abnormal auditory P300 topography and positive symptoms in schizophrenia: a preliminary report.

P300 component amplitude in the left temporal scalp region, shown in three previous studies to differentiate normals from schizophrenics, was found to be significantly correlated with the Thought Disorder Index (TDI) and the Scale for the Assessment of Positive Symptoms (SAPS). These correlations occurred primarily in the P300 waveform derived from the Goodin paradigm. These findings suggest a brain processing disturbance in positive symptom schizophrenia that may be reflected by electrophysiological abnormalities detectable in the temporal scalp region.

Elevated motor threshold in drug-free, cocaine-dependent patients assessed with transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a noninvasive method of examining cortical inhibitory and excitatory processes and cortical excitability in awake subjects. There is evidence from clinical and electroencephalographic (EEG) data that cortical excitability may be abnormal in some psychiatric populations. Chronic cocaine abuse influences a number of neurotransmitters that are involved in the excitatory/inhibitory balance of the cerebral cortex. This pilot study was conducted to ascertain the possible utility of TMS in examining cortical excitability in a population of chronic cocaine abusers. METHODS: The right and left motor thresholds of ten cocaine-dependent subjects, according to DSM-IV, and ten normal control subjects were examined using single pulse TMS. RESULTS: The resting motor thresholds resulting from stimulation of the right or the left motor cortical regions were significantly elevated in cocaine-dependent subjects compared with matched control subjects. CONCLUSIONS: These pilot data suggest that chronic cocaine use significantly alters cortical excitability in the direction of increased inhibition or decreased excitability. We hypothesize that this observation reflects adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures.

Event-related brain potentials in depressed patients treated with electroconvulsive therapy.

1. As impairment of attention has long been recognized as a clinical feature of depression, we undertook to evaluate in depressed subjects and controls a feature of the event-related brain potentials (ERP) the N100 wave which has been linked to attentional processes. 2. This study involved collection of EEG data in an "auditory oddball" ERP paradigm in 9 depressed subjects prior to and following a course of 6 electroconvulsive therapy (ECT) treatments, as well as 11 controls. Concurrent Hamilton depression rating scales provided a measure of symptomatic severity. 3. Pretreatment N100 amplitude was significantly lower in the depressed group while N100 latency was greater than among controls, with treatment differences from control values disappeared. Further a robust correlation (r = 0.85 p less than or equal to .0038) emerged between N100 amplitude (increased amplitude being lower) and severity of depression. 4. Those results provide evidence for a physiological attentional disturbance in depression and suggest that certain features of this disturbance relate directly to symptom severity.

An atlas of the deep cerebellar nuclei and subtentorial brainstem of the cat with compensation for skull-size.

The bony tentorium in the cat precludes a stereotaxic approach, in the coronal plane, to widespread areas of the cerebellum and underlying brainstem. To facilitate the application of the stereotaxic method in these areas, an atlas of the subtentorial brainstem was prepared, with plates (30 degrees from the vertical) based on an angle of entry which avoids the tentorium. In addition, a placement error regression function, based on a measure of skull size, was derived to provide atlas coordinate corrections for different brain sizes. The application of this regression function, together with the present atlas plates, can greatly increase placement accuracy.

Evoked potentials in subjects at risk for Alzheimer's disease.

Evoked potential (EP) changes accompanying dementing processes have been documented in a number of studies. However, EPs have not been studied in subjects who are at heightened risk for the development of Alzheimer's Disease (AD). Nineteen volunteers with no immediate family members with a history of AD and 33 healthy subjects with at least one first-degree relative with AD were studied. Of the 33 subjects with a positive family history of AD, the illness of the sick relative was classified as possible AD in 10 subjects, probable AD in 17 subjects, and definite (autopsy-proven) AD in 6 subjects. Mid-latency evoked potentials (P50, N100, and P200) and P300 event-related potentials were recorded in an oddball paradigm. The amplitudes of the P50 responses to the frequent stimuli and of the P300 responses were significantly higher in the subjects whose relatives had definite AD as compared with the other three groups. The amplitude of the N100 component was also larger in the same group, but the difference was only statistically significant from the group of healthy volunteers without a family history of AD. A process of increased sensitivity to incoming stimuli may be reflected in the increased P50, N100, and P300 amplitudes in the subjects at increased risk for developing AD.

Auditory evoked potentials, clinical vs. research applications.

Evidence of abnormal auditory evoked potentials (EPs) in patients suffering from schizophrenia has been accumulating. In spite of the magnitude of the EPs in schizophrenia literature, EPs have not been found to be clinically useful thus far. In this study we attempted to replicate the findings in a large sample of schizophrenia patients, and describe how auditory EPs may be used as supplemental tests in the differential diagnostic process. Five subject groups were formed; paranoid (PAR) and disorganized/undifferentiated (disorg/undiff) schizophrenics, schizoaffective (SA), bipolar, and a normal control group. All patients were stable on medications. Subjects underwent one EP recording session. Classification and regression trees (CART) based on EP amplitudes were used to classify subjects into subgroups. The optimal Bayes classification rule that minimizes the expected misclassification cost was then constructed for various misclassification cost functions. In a standard 'Odd Ball' paradigm the N100 amplitudes were significantly decreased in the disorg/undiff group than in the bipolar or normal subjects. The P200 amplitude was smaller in the PAR, disorg/undiff and the SA groups than in the normal controls. Both the disorg/undiff and the PAR groups had significantly lower P300 amplitudes than the normal controls. Classification rules used to classify subjects into normal or ill were sensitive to the relative cost of misclassifying a subject, as well as the prior clinical probability that this subject was ill. Our data largely agree with the existing literature showing abnormally decreased N100, P200, and P300 amplitudes in schizophrenic patients, particularly the disorg/undiff patients. We conclude that whether EP measures are clinically useful depends on the clinical situation. In particular, the prior probability of the diagnosis in question being present and the cost of misclassifying the patient are critical.