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.

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.

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.

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.

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.

Prevention of multiple pregnancy following IVF in Spain.

Since the development of assisted reproduction techniques most countries have witnessed increased rates of multiple pregnancy. Despite the guidelines proposed by various scientific societies these rates continue to be abnormally high. In Spain, as in other Mediterranean countries, a greater number of embryos are transferred than in northern and central European countries and the incidence of multiple pregnancies is greater in comparison. Effective strategies must be established to prevent multiple pregnancy without reducing overall pregnancy rates. In the authors' institute, taking into account the authors' experience, the relevant literature, and despite the limitation of retrospective studies, it is recommended that a maximum of two embryos are transferred in young women with good quality embryos at the time of transfer. The transfer of three embryos is only recommended in women >or=38 years who have one or no good quality embryos available at the time of transfer. The responsibility for preventing multiple pregnancy lies with health professionals, who must be aware of the risks involved in twin and triplet pregnancy. Couples must be provided with objective information before starting an IVF cycle. Professional societies should highlight the problem and make suitable recommendations.

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.

Restored antioxidant capacity parallels the immunologic and virologic improvement in children with perinatal human immunodeficiency virus infection receiving highly active antiretroviral therapy.

CD3+CD4+ T-lymphocyte numbers, viral load, and serum antioxidant capacity were evaluated in 20 children with perinatal human immunodeficiency virus (HIV) infection one month (T = -1) and one day (T = 0) before and one month (T = 1) and two months (T = 2) after a treatment switch to highly active antiretroviral therapy (HAART). Antioxidant capacity micromol/L) was evaluated by measuring the cuprous ion deriving from a known amount of cupric ion. Compared to control values (998 +/- 113 micromol/L), values in HIV-infected children were lower before HAART (T = -1, 848 +/- 211 micromol/L, P = 0.008; T = 0, 732 +/- 131 micromol/L, P < 0.0001), but similar during HAART (T = 1, 914 +/- 121 micromol/L, P = 0.089; T = 2; 957 +/- 155 micromol/L, P = 0.528; T = 1 and T = 2 vs T = 0, P < 0.0001). Immunologic and virologic improvement paralleled the restored antioxidant capacity. HAART may restore antioxidant capacity suppressing HIV, which inhibits antioxidant capacity. A positive feedback may be triggered since restored antioxidant capacity counterbalances the oxidative stress, which enhances lymphocyte apoptosis and HIV replication.

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.

Antiproliferative effects of insulin-like growth factor-binding protein-3 in mesenchymal chondrogenic cell line RCJ3.1C5.18. relationship to differentiation stage.

Chondrogenesis results from a complex equilibrium between chondrocyte proliferation and differentiation. Insulin-like growth factors (IGFs) have a crucial role in chondrogenesis, but their mechanisms of action are not well defined. IGF-binding protein-3 (IGFBP-3) is the major carrier for circulating IGFs in postnatal life, and has been shown to have IGF-independent effects on proliferation of several cancer cell lines. In this study, we have evaluated the IGF-independent and -dependent effects of IGFBP-3 on chondrocyte proliferation and the relationship of these effects with chondrocyte differentiation stage. We used the RCJ3.1C5.18 nontransformed mesenchymal chondrogenic cell line, which, over 2 weeks of culture, progresses through the differentiation pathway exhibited by chondrocytes in the growth plate. We demonstrated that IGFBP-3 inhibited, in a dose-dependent manner (1-30 nm), the proliferation of chondroprogenitors and early differentiated chondrocytes, stimulated by des-(1-3)-IGF-I and longR(3)-IGF-I (IGF-I analogs with reduced affinity for IGFBP-3), and by insulin and IGF-I. In terminally differentiated chondrocytes, IGFBP-3 retained the ability to inhibit cell proliferation stimulated by IGF-I, but had no effect on cell growth stimulated by insulin, or des-(1-3)-IGF-I or longR(3)IGF-I. By monolayer affinity cross-linking, we demonstrated a specific IGFBP-3-associated cell-membrane protein of approximately 20 kDa. We determined that IGFBP-3 has an antiproliferative effect on chondrocytes and, that this effect is related to the differentiation process. In chondroprogenitors and early differentiated chondrocytes, antiproliferative effect of IGFBP-3 is mainly IGF-independent, whereas, following terminal differentiation this effect is IGF-dependent.

Similarities in the disturbances in cortical information processing in alcoholism and aging: a pilot evoked potential study.

OBJECTIVE: To examine the hypothesis that chronic alcohol use causes accelerated aging of the brain. METHODS: The auditory evoked potentials (EPs) were compared in three groups of 10 subjects each: (a) middle-aged individuals meeting DSM-IV criteria for alcohol dependence, (b) age- and gender-matched group of healthy individuals, and (c) an older (>65 years) group of gender-matched healthy individuals. Multiple levels of cortical information processing were examined using EPs. Early stages of information processing, related to sensory gating and stimulus classification (P50, N100/P200), were studied using a paired-click paradigm. Later stages of information processing associated with memory upgrading and identification of novel stimuli (P300) were studied using an oddball paradigm. RESULTS: The amplitude and latency of the P300 of the alcoholic patients and the older healthy subjects differed significantly from those of the younger healthy group. Both groups showed changes that have been reported in association with aging. A tendency towards decreased sensory gating in later stages of information processing was noted in the aged healthy individuals. CONCLUSIONS: These data suggest that alcohol dependence may accelerate the aging process. The tendency towards a sensory gating deficit during the attentive phase of information processing in older healthy subjects requires further investigation because it may be a marker for an increased proneness to developing psychotic symptoms in that group.

HLA-C and HLA-DQB1 compatibility in unrelated cord blood transplants.

BACKGROUND AND OBJECTIVE: Umbilical cord blood (UCB) cells have been definitively proved to be a source of hematopoietic stem cells with repopulating capacity when transplanted into pediatric hosts with neoplastic or non-neoplastic disease. Moreover, due to the immaturity of the UCB lymphoid compartment, these transplants are usually associated with a low incidence and severity of GvHD. This clinical observation and the immaturity of the UCB lymphoid compartment justify the acceptance of UCB units which differ from their recipient by 1 or 2 HLA antigens of the six HLA A, B and DRB1 antigens conventionally typed. Whether the number and type of HLA disparities affect clinical outcome of UCB transplants has not, however, been clearly demonstrated yet. DESIGN AND METHODS: In the present study on 14 pediatric patients with high risk leukemia transplanted with UCB from unrelated donors, evaluation of HLA compatibility was extended to HLA-C and DQB1 genes and correlated to the engraftment rate and occurrence of GvHD. Conditioning regimen and GvHD prophylaxis were identical in all cases. HLA-A and B antigens were typed by serology, whereas DNA based methods were used to define HLA-C gene groups, and HLA-DRB1 and DQB1 alleles. RESULTS: Conventional HLA-A, B and DRB1 typing demonstrated that 12 recipient/donor pairs differed at one HLA locus, while 2 pairs had 2 HLA disparities. The extended HLA-typing showed that only one out of the six pairs with a different HLA-A locus had additional mismatches at HLA-C and DQB1 loci, whereas all the remaining 8 pairs, which already differed at HLA-B and/or DRB1 loci after conventional typing, had additional HLA-C and/or DQB1 mismatches (p = 0.002). By contrast, engraftment rate and occurrence of GvHD did not significantly correlate with level of HLA-mismatches even after extended HLA-typing. INTERPRETATION AND CONCLUSIONS: The present data show that additional mismatched HLA-C and/or DQB1 antigens are significantly more frequent in pairs which after conventional HLA-typing differed at HLA-B and/or DRB1 loci, than in those showing one HLA-A mismatch. This observation provides an additional criterion for selection of UCB donors with the closest HLA-match when more than one unit are available. We did not, however, observe any correlation between engraftment rate, occurrence of GvHD and degree of HLA disparities detected either by standard or extended typing. These data support the notion that certain HLA differences do not affect the clinical outcome of UCB transplants and indicate that the expensive and time consuming molecular typing of HLA-C and DQB1 loci might be avoided for UCB donor selection.

Use of co-culture of human embryos on Vero cells to improve clinical implantation rate.

Co-culture of human embryos (n = 384 cycles) to the blastocyst stage using Vero cell monolayers was carried out between August 1995 and December 1997. A total of 2868 zygotes were co-cultured and 1027 embryos reached the blastocyst stage (blastocyst formation rate 35.8%). The blastocysts were frozen in 43.7% of patients. A mean of 1.8 blastocysts was transferred per patient and 95 pregnancies were obtained (pregnancy rate/cycle 24.7%). The blastocyst implantation rate was 23.6%. Miscarriage occurred in 15 patients (15.7%) and ectopic pregnancy in three (3.1%) patients. The multiple pregnancy rate was 32.6%. No differences were observed in the blastocyst rate between poor, normal or high response patients. Blastocyst formation was significantly lower when frozen donor spermatozoa were used. Significantly higher pregnancy rates per transfer and blastocyst implantation rates were attained when embryos were transferred on days 5 or 6 compared with day 7. No advantage was observed when co-culture was used in first cycle IVF patients, in comparison with conventional day 2 replacements. The use of blastocysts for preimplantation genetic diagnosis (PGD) increases the diagnostic reliability and widens diagnostic possibilities. A total of 215 cycles with frozen-thawed co-cultured blastocysts were carried out, with a pregnancy rate of 22.7% per replacement.

Auditory event-related potentials and statistical probability mapping in obsessive-compulsive disorder.

The current exploratory investigation was undertaken to replicate and extend previous findings of auditory event related potentials (ERPs) observed in obsessive-compulsive disorder (OCD). Similar to previous ERP studies, this study revealed a decreased slow wave (SW) (post P300) latency, a trend towards decreased P300 latency and a greater N200 amplitude in OCD subjects than in controls. In addition, the chronicity of OCD symptoms was correlated with the 140-170 millisecond integrated amplitude and the severity of OCD symptoms correlated with the 386-438 millisecond integrated amplitude. Current findings lend additional support to evidence suggesting OCD represents, in part, hyperarousal of the cortex.