bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytoprotective and anti‐inflammatory effects of melatonin in hydrogen peroxide‐stimulated CHON‐001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway
Authors: Lim Hyun‐Dae , Kim Young‐Suk , Ko Seok‐Ho , Yoon In‐Jong , Cho Seong‐Guk , Chun Yang‐Hyun , Choi Byeong‐Jun , Kim Eun‐Cheol
Published: March 2012

Abstract:  Melatonin has potent antioxidant, analgesic, and antinociceptive properties. However, the effects of melatonin against oxidative stress‐induced cytotoxicity and inflammatory mediators in human chondrocytes remain poorly understood. This study examined the effects and underlying mechanism of melatonin in hydrogen peroxide (H2O2)‐stimulated human chondrocytes and rabbit osteoarthritis (OA) model. Melatonin markedly inhibited hydrogen peroxide (H2O2)‐stimulated cytotoxicity, iNOS, and COX‐2 protein and mRNA expression, as well as the downstream products, NO and PGE2. Incubation of cells with melatonin decreased H2O2‐induced Sirtuin 1 (SIRT1) mRNA and protein expression. SIRT1 inhibition by sirtinol or Sirt1 siRNA reversed the effects of melatonin on H2O2‐mediated induction of pro‐inflammatory cytokines (NO, PGE2, TNF‐α, IL‐1β, and IL‐8) and the expression of iNOS, COX‐2, and cartilage destruction molecules. Melatonin blocked H2O2‐induced phosphorylation of PI3K/Akt, p38, ERK, JNK, and MAPK, as well as activation of NF‐κB, which was reversed by sirtinol and SIRT1 siRNA. In rabbit with OA, intra‐articular injection of melatonin significantly reduced cartilage degradation, which was reversed by sirtinol. Taken together, this study shows that melatonin exerts cytoprotective and anti‐inflammatory effects in an oxidative stress‐stimulated chondrocyte model and rabbit OA model, and that the SIRT1 pathway is strongly involved in this effect.
Melatonin reduces lung oxidative stress in patients with chronic obstructive pulmonary disease: a randomized, double‐blind, placebo‐controlled study
Authors: de Matos Cavalcante Antonio George , de Bruin Pedro Felipe Carvalhedo , de Bruin Veralice Meireles Sales , Nunes Deuzilane Muniz , Pereira Eanes Delgado Barros , Cavalcante Marina Medeiros , Andrade Geanne Matos
Published: March 2012

Abstract:  Chronic obstructive pulmonary disease (COPD), a major cause of death and disability, is attributed to an abnormal inflammatory response by the lungs to noxious substances, primarily from cigarette smoke. Although oxidative stress is regarded as central to the pathogenesis of COPD, very few studies have examined the effects of antioxidants in this condition. This was a randomized, double‐blind, placebo‐controlled study on the effects of melatonin in COPD. Thirty‐six consecutive patients with clinically stable moderate to very severe COPD (30 men; mean ± S.D. = 66.6 ± 7.8 yr) were randomized to receive 3 mg melatonin (N = 18) or placebo for 3 months. Oxidative stress was evaluated by 8‐isoprostane levels in exhaled breath condensate at baseline (T0) and after one (T1), two (T2), and three months (T3) of treatment. Additionally, exhaled breath condensate levels of IL‐8, dyspnea severity (Medical Research Council scale), lung function (spirometry), and functional exercise capacity (six min walk test) were compared at baseline and after treatment. Patients receiving melatonin showed a decrease in 8‐isoprostane (T0: mean ± S.E.M. = 20.41 ± 2.92 pg/mL; T1: 18.56 ± 2.68 pg/mL; T2: 12.68 ± 2.04 pg/mL; T3: 12.70 ± 2.18 pg/mL; P = 0.04; repeated measures ANOVA) with significant differences from baseline after 2 (P = 0.03) and 3 months (P = 0.01). Dyspnea was improved by melatonin (P = 0.01), despite no significant changes in lung function or exercise capacity. Placebo‐treated patients, but not those who were given melatonin, showed an increase in IL‐8 (P = 0.03). In summary, melatonin administration reduced oxidative stress and improved dyspnea in COPD. Further studies are necessary to determine the potential role for melatonin in the long‐term management of these patients.
Melatonin regulates Arabidopsis root system architecture likely acting independently of auxin signaling
Authors: Pelagio‐Flores Ramón , Muñoz‐Parra Edith , Ortiz‐Castro Randy , López‐Bucio José
Published: March 2012

Abstract:  Melatonin (N‐acetyl‐5‐methoxytryptamine) is a tryptophan‐derived signal with important physiological roles in mammals. Although the presence of melatonin in plants may be universal, its endogenous function in plant tissues is unknown. On the basis of its structural similarity to indole‐3‐acetic acid, recent studies mainly focusing on root growth in several plant species have suggested a potential auxin‐like activity of melatonin. However, direct evidence about the mechanisms of action of this regulator is lacking. In this work, we used Arabidopsis thaliana seedlings as a model system to evaluate the effects of melatonin on plant growth and development. Melatonin modulated root system architecture by stimulating lateral and adventitious root formation but minimally affected primary root growth or root hair development. The auxin activity of melatonin in roots was investigated using the auxin‐responsive marker constructs DR5:uidA, BA3:uidA, and HS::AXR3NT‐GUS. Our results show that melatonin neither activates auxin‐inducible gene expression nor induces the degradation of HS::AXR3NT‐GUS, indicating that root developmental changes elicited by melatonin were independent of auxin signaling. Taken together, our results suggest that melatonin is beneficial to plants by increasing root branching and that root development processes elicited by this novel plant signal are likely independent of auxin responses.
Heat shock protein 27 expression in areca quid chewing‐associated oral squamous cell carcinomas
Authors: Lee S‐S , Tsai C‐H , Ho Y‐C , Yu C‐C , Chang Y‐C
Published: March 2012

Oral Diseases (2012) 18, 713–719

Objectives:  Heat shock protein (HSP) 27 is a low‐molecular‐weight protein that functions as a molecular chaperone and plays a cytoprotective role through its antioxidant activity during cell stress. Areca quid chewing is associated with the high incidence of oral squamous cell carcinomas (OSCCs) in Taiwan. The aim of this study was to compare heat shock protein 27 (HSP27) expression in OSCCs and the normal oral tissues.

Methods:  Forty‐eight OSCCs from areca quid chewers and ten normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry for HSP27. The normal human oral keratinocytes (HOKs) were challenged with arecoline, the major alkaloid of areca nut, by Western blot for HSP27. Furthermore, epigallocatechin‐3 gallate (EGCG), glutathione precursor N‐acetyl‐l‐cysteine (NAC), cyclooxygenase‐2 inhibitor NS‐398, HSP inhibitor quercetin, extracellular signal‐regulated protein kinase (ERK) inhibitor PD98059, and p38 inhibitor SB203580 were added to find the possible regulatory mechanisms.

Results:  Heat shock protein 27 exhibited higher expression in OSCCs than normal specimens (P <   0.05). Arecoline was found to elevate HSP27 expression in a dose‐ and time‐dependent manner (P <   0.05). The additions of pharmacological agents were found to inhibit arecoline‐induced HSP27 expression (P < 0.05).

Conclusions:  Heat shock protein 27 expression is significantly elevated in areca quid chewing‐associated OSCCs. Arecoline‐induced HSP27 expression was downregulated by EGCG, NS398, NAC, quercetin, PD98059, and SB203580.
Parkinson’s disease: considerations for dental hygienists
Authors: DeBowes SL , Tolle SL , Bruhn AM
Published: March 2012

Abstract:  The prevalence of Parkinson’s disease (PD) is expected to double over the next 20 years owing to the increase in life expectancy. This progressive disease has several implications relating to oral health, and many are manageable with proper awareness and knowledge about the disease. This article reviews the epidemiology, pathophysiology, and characteristics of PD, as well as the treatments and oral health considerations to enable dental hygienists to undertake an informed approach to patient management strategies and provide optimal care.
Inhaled nitric oxide in neonates and children with pulmonary hypertension
Authors: Lönnqvist PA , Winberg P. , Lundell B. , Selldén H. , Olsson GL
Published: March 2012

Fourteen critically ill neonatal and paediatric intensive care patients with various primary diagnoses and signs of associated pulmonary hypertension received inhaled nitric oxide (NO), 20–80 ppm, after failure of conventional therapy to improve oxygenation. NO administration was found to be associated with a significant improvement in postductal arterial oxygen tension (pre‐NO: 3.75 (SD 1.39) kPa; post‐NO: 6.05 (SD 1.70) kPa; p = 0.004). In 10 patients, NO was found to increase arterial oxygen tension with more than 1 kPa. In 2 of these patients, ECMO treatment could be avoided due to the pronounced improvement in gas exchange seen after the initiation of NO administration. The remaining 4 patients failed to respond to NO administration. One patient developed methaemoglobinaemia (13.9%) which required treatment with methylthionine. Since we were unable to produce any beneficial effect of NO in the late phase of the pulmonary disease process, we believe that, in order to be successful, inhaled NO should be instituted when conventional treatment has failed and the administration of an iv vasodilator is usually considered.
Prevalence of specific antibodies to Chlamydia pneumoniae in children with acute respiratory infections
Authors: Lund‐Olsen I. , Lundbäck A. , Gnarpe J. , Gnarpe H.
Published: March 2012

We investigated 56 boys and 30 girls between the ages of 1 month and 15 years with acute respiratory infections for antibodies to Chlamydia pneumoniae and Mycoplasma pneumoniae. Antibodies were only occasionally found in children less than 10 years of age (4% of boys (1/23) and 5% of girls (1/19). In the age group 10–12 years, antibodies were detected in 55% of boys (4/9) but not in the 2 girls investigated. In the age group 13–15 years, antibodies were detected in 58% of boys (14/24) and in 33% of girls (3/9). Infection caused by M. pneumoniae was found in 13% of boys in the oldest age group.□
Eosinophil cationic protein in nasal secretion and in serum and myeloperoxidase in serum in respiratory syncytial virus bronchiolitis: relation to asthma and atopy
Authors: Sigurs N. , Bjarnason R. , Sigurbergsson F.
Published: March 2012

Eosinophil cationic protein (ECP) in nasal secretions was determined in 34 infants with respiratory syncytial virus (RSV) bronchiolitis during the acute infection stage and one and six months later. ECP in serum was determined in 19 of these children at the same time. Myeloperoxidase (MPO) was determined in the same 19 children at the acute infection stage and after one month. All children were followed prospectively for two years after the infection with regard to the development of bronchial obstructive symptoms. Asthma, defined as three or more episodes of bronchial obstruction verified by a physician, developed in 18% of children and less severe obstructive symptoms in 29%. A screening test for food IgE antibodies in serum was performed six months and a skin prick test two years after the acute infection. Nasal ECP/albumin ratios after six months were significantly higher than during the acute RSV infection. MPO, but not ECP, levels in serum were significantly elevated at the time of acute infection compared with levels after one month. Nasal ECP/albumin ratios at the acute infection were compared to a control group of 27 infants with non‐RSV upper respiratory tract infections and did not differ. It was not possible to predict, either from ECP/albumin ratios in nasal secretion or from ECP and MPO in serum, which children would develop asthma, other bronchial obstructive symptoms or positive IgE tests.
Changes in craniofacial development induced by growth hormone therapy in children treated with bone marrow transplantation
Authors: Dahllöf G. , Forsberg CM , Borgström B.
Published: March 2012

The effect of growth hormone (GH) treatment on craniofacial development was studied in nine children exhibiting low growth velocity after bone marrow transplantation (BMT). Comparisons were made with seven BMT children who had not received GH. Two groups of age‐ and sex‐matched healthy children served as controls for the respective patient groups. After an average observation period of 3.5 years, the BMT children not treated with GH exhibited significantly reduced mandibular length and alveolar height (p < 0.01). The increase in mandibular length was only 30% of that found in healthy controls. Maxillary growth was less affected by BMT treatment. In the GH treated group, no significant differences were found in craniofacial growth increments compared with controls. Although exogenous GH therapy in this group of children did not induce a catch‐up growth, it appears to have prevented further loss in growth potential.
Treatment effects in Trichuris dysentery syndrome
Authors: Callender JE , Grantham‐McGregor SM , Walker SP , Cooper ES
Published: March 2012

Heavy infection with the geohelminth Trichuris trichiura causes the Trichuris dysentery syndrome (TDS). Growth retardation and anaemia are characteristic of TDS and both are associated with poor development. We have examined the growth and developmental responses to treatment in 19 children aged 27–84 months with TDS. Developmental levels (DQ) were measured with the Griffiths mental development scales. Compared with a control group matched for age, gender and neighbourhood, the TDS children initially had serious deficits in DQ (24 points, p < 0.001). After a year of anthelmintic treatment, the TDS children showed improvement in locomotor development (p < 0.001) compared with the controls. The TDS children also had initial deficits in height‐for‐age, weight‐for‐height, mid‐upper arm circumference and haemoglobin levels. They caught up rapidly in indices of wasting (weight‐for‐height and mid‐upper arm circumference) and showed steady improvement in height‐for‐age and haemoglobin levels. Catch‐up in height was comparable to that of children recovering from coeliac disease. The importance of continuing prevention after initial treatment is highlighted.
Successful treatment of aortic thrombosis after umbilical catheterization with tissue plasminogen activator
Authors: Ahluwalia JS , Kelsall AWR , Diederich S. , Rennie JM
Published: March 2012

An infant presented 10 days after removal of a high umbilical arterial catheter with total occlusion of the distal abdominal aorta. Complete dissolution was achieved with a combination of iv tissue plasminogen activator and heparin. Ultrasound examination confirmed the diagnosis and subsequent resolution of the thrombus.
Early neonatal renal venous thrombosis: long‐term outcome
Authors: Keidan I. , Lotan D. , Gazit G. , Boichis H. , Reichman B. , Linder N.
Published: March 2012

Renal venous thrombosis was diagnosed in the first week of life in 6 of 30 101 live infant births born at the Chaim Sheba Medical Center in Israel from 1984 to 1989. The thrombosis was unilateral in 5 neonates and bilateral in 1. Predisposing maternal risk factors included 2 cases of maternal diabetes and 1 case of maternal hypertension with associated intrauterine growth retardation. Perinatal risk factors included 2 cases of prematurity with severe hyaline membrane disease, 1 infant who was small for gestational age and another with asphyxia. Follow‐up for 1–5 years following the acute event revealed normal growth and development in all infants. None of the patients was hypertensive and all had normal renal glomerular and tubular functions. Renal imaging and scan studies revealed loss of perfusion in 4 atrophic kidneys and diminished perfusion in the remaining 2. In conclusion, although renal venous thrombosis in neonates is associated with low mortality, long‐term dysfunction in the affected kidney is common.
Reactive arthritis due to Salmonella enteritidis complicated by carditis
Authors: Huppertz HI , Sandhage K.
Published: March 2012

Reactive arthritis following infection with enteropathogenic bacteria is usually a self‐limiting disease that disappears after a few months without sequela. We describe two girls who developed carditis shortly after the onset of reactive arthritis due to infection with Salmonella enteritidis. The carditis presented with fatigue and arrhythmia and involved the aortic valve in both patients leading to definite aortic regurgitation in one. A similar pattern of cardiac involvement is found in other spondyloarthropathies, including Reiter's syndrome and ankylosing spondylitis. We conclude that Salmonella reactive arthritis may be complicated by carditis.
Growth and subcutaneous fat during the first five years of insulin‐dependent diabetes in children
Authors: Tuvemo T. , Kobbah M. , Proos LA
Published: March 2012

Thirty‐four children were observed prospectively during a period of 5 years from the onset of diabetes regarding height, weight and subcutaneous fat in relation to treatment and diabetes control. Height, weight and body mass index (BMI) did not differ from those in a control group. The girls with diabetes increased their triceps and subscapular fat significantly despite a normal BMI. This increase in relation to control girls was most pronounced during late adolescence. Triceps skinfold and BMI after 5 years were both negatively correlated to insulin dose per kilogram body weight in the diabetic girls. We conclude that girls with diabetes accumulate subcutaneous fat in certain areas rapidly during adolescence in a completely different way from healthy girls.
Vascular reactivity and platelet aggregability during the first five years of insulin‐dependent diabetes in children
Authors: Ewald U. , Kobbah M. , Tuvemo T.
Published: March 2012

Skin microvascular reactivity and platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied prospectively in a population‐based cohort of children with newly acquired type 1 diabetes mellitus (IDDM), who have now been followed up longitudinally for 5 years. The skin microvascular vasodilation in response to ischaemia was recorded by means of transcutaneous oximetry at 37°C and compared with that in a control group of 58 healthy children. Platelet aggregation was compared with 42 healthy control children. Sixty months after diagnosis, the same degree of impairment of vasodilatory capacity was noted as previously recorded at 24 months and on admission, on all these occasions being significantly lower than the control value and the results from the 12‐month follow‐up. A sex difference was noted, diabetic girls both during and after puberty exhibiting a greater impairment of vasodilator capacity as compared with diabetic boys. The same degree of platelet aggregation in response to collagen was noted 60 months after diagnosis as had been recorded previously at 24 and 12 months, all significantly increased as compared with the results from admission, but not different from those in controls. By contrast, the aggregation in response to ADP was now lower than that observed on admission. No statistically significant gender difference was noted. The implication of the impaired skin microvascular vasodilation and of the changing pattern of platelet aggregation for later diabetic angiopathy needs to be evaluated in the coming decade.
Diagnosis of intracranial lesions in very‐low‐birthweight infants by ultrasound: incidence and association with potential risk factors
Authors: Hesser U. , Katz‐Salamon M. , Mortensson W. , Flodmark O. , Forssberg H.
Published: March 2012

This study was designed to determine the frequencies of germinal matrix and ventricular haemorrhages as well as lesions in the white matter diagnosed by ultrasonography. In subsequent studies the effects of perinatal brain lesions on the cognitive and motor development of preterm children will be presented. Lesions of the white matter are probably more damaging than intraventricular and subependymal bleeds. Therefore, a modified classification of the lesions was used, clearly separating bleeds from white matter pathology. The study includes 291 infants with a body weight of ≤1500 g consecutively admitted to the neonatal intensive‐care unit at Karolinska Hospital from 1988 to 1993. Fifty‐four (18.9%) died before 6 months. Two hundred and sixty‐three infants were examined using ultrasound. Pathology due to bleeding was classified into three grades (B1–3) similar to Papile's first three grades. Pathology in periventricular white matter was classified into four groups (W1–4): W1 = subtle and W2 = distinctive white matter echodensities; W3 = cyst formation; W4 = large, intense echodensity. Forty‐nine patients had abnormalities in the periventricular white matter (15 W1, 12 W2, 11 W3 and 11 W4) and 58 had subependymal (B1 = 29) or ventricular bleeding without (B2 = 13) or with dilatation (B3 = 16). Ventilator treatment was significantly associated with both B and W lesions. Low gestational age, low birthweight, small for gestational age, pre‐eclampsia and caesarean section were significantly associated with B lesions whereas asphyxia, surfactant treatment, male patient sex and outborn were associated with W lesions; B1–3 and W1–4 lesions were thus partly associated with different potential risk factors. The pre‐ and perinatal potential risk factors could only partly explain the variance in the frequency of B and W lesions, indicating that there are yet unidentified risk factors for intracranial ultrasonographic pathology.
Viral phenotype in mother‐to‐child HIV‐1 transmission and disease progression of vertically acquired HIV‐1 infection
Authors: De Rossi A. , Ometto L. , Masiero S. , Zanchetta M. , Chieco‐Bianchi L.
Published: March 2012

Human immunodeficiency virus‐1 (HIV‐1) primary isolates differ in replicative capacity on peripheral blood mononuclear cells, tropism for primary monocyte‐derived macrophages (MDM) and T‐cell lines and syncytium‐inducing (SI) capability on MT‐2 cells in vitro. To assess the role of viral phenotype in mother‐to‐child HIV‐1 transmission and the progression of vertically acquired HIV‐1 infection, we studied 57 HIV‐1‐infected women at the time of delivery and 24 HIV‐1‐infected infants. Eight mothers transmitted the infection to their children. Primary isolates, obtained from 7 and 33 transmitting and non‐transmitting mothers, respectively, differed in replicative capacity and SI activity, and no significant differences between the two groups were found regarding these viral properties. However, all primary isolates from transmitting mothers, but about half of those from non‐transmitting mothers, were able to infect and replicate in MDM, regardless of their replicative capacity and/or SI activity; moreover, the monocyto‐macrophage tropism of the maternal isolate correlated with an increased risk of transmission.

Viral isolates from HIV‐1‐infected children were typed before 2 months of age; all but four showed a tropism for MDM, further supporting the notion that monocyto‐macrophage tropic variants are selectively transmitted from mother to child and/or selectively replicated upon transmission. Clinical follow‐up disclosed that 7/11 infants with a rapid/high replicating virus but none of the 17 with a slow replicating virus developed severe symptoms of disease and/or severe immunodepression by 1 year of age. By means of competitive RNA‐polymerase chain reaction (PCR), a relationship was found between viral phenotype and dynamics of HIV‐1 replication early in life in children who experienced different patterns of disease progression.
Anonymous testing of newborn infants for HIV antibodies as a basis for estimating prevalence of HIV in childbearing women: the 1991–1994 study in Spain
Authors: Canosa CA , Grady GF , Cabello ML , Comeau AM , Schwerzler ME , Contreras MT , Fraga JM , de los Terreros I. Gomez , Peňa J.
Published: March 2012

During 1991–1994, anonymous screening of newborn infants for maternal antibody to human immunodeficiency virus (HIV) was carried out in three regions of Spain: Valencia, Galicia and Sevilla. The newborn infants whose heel‐stick blood eluates were satisfactory for HIV antibody tests were a consecutive series of 104 876, representing 99.3% of all newborn infants undergoing routine metabolic screening and estimated as comprising at least 98% of all births in the three regions. Enzyme immunoassay (EIA) positives were confirmed by immunoblot, yielding 246 confirmations: a rate of 2.3 per 1000. Seropositivity rates ranged from 1.4 per 1000 in Galicia to 2.1 in Sevilla and 3.1 in Valencia, and remained relatively stable in each region during the years of the study. Within socioeconomically defined subgroups of birth hospitals in Valencia and Galicia, all subgroups contained seropositives, even though there was a twofold to fivefold over‐representation in the “inner city” public hospitals. To estimate the proportion of HIV‐1‐seropositive newborn infants who were positive for HIV‐1 DNA, polymerase chain reaction (PCR) assays were performed on 165 dried blood spots that had been retained following positive immunoblot assays. Fifteen (9%) were PCR positive, and when this proportion is adjusted for the age‐specific sensitivity of the method, it translates into an estimated HIV‐1 transmission rate of 24% (range 18–36%). For 94 906 of the 104 876 newborn infants screened, the EIA used could detect antibodies that react with epitopes of HIV‐1 and HIV‐2. There were 30 newborn infants whose blood eluate was positive by this combined HIV‐1/HIV‐2 antibody screen and whose secondary screening with monovalent HIV‐2 and HIV‐1 EIA indicated that the HIV‐2 reactivity was above the cut‐off whereas the HIV‐1 was not. Ranking these 30 results according to absolute HIV‐2 reactivity and relative reactivity with respect to HIV‐1 indicated that four infants were probable true HIV‐2 seropositives and a total of 12 were possible HIV‐2 seropositives, a prevalence of the order of 1:10000 to 1:20000 newborn infants. These anonymous population‐based serological studies provide “leading‐indicator” data to complement traditional AIDS surveillance for epidemiological and planning purposes.
Progress in prevention of perinatal HIV‐1
Authors: Fowler MG , Mofenson L.
Published: March 2012

The findings of a recent human immunodeficiency (HIV‐1) prevention trial in the USA demonstrated that administration of an antiretriviral drug, zidovudine, to mothers during the prenatal and intrapartum periods, and to their neonates for 6 weeks, resulted in a two‐thirds reduction in risk of perinatal transmission from 25.5% to 8.3%. These results were rapidly disseminated both in the USA and internationally. Since the release of these clinical trial results in the spring of 1994, several observational studies have documented a sharp increase in maternal and neonatal zidovudine use, as well as a significant decrease in perinatal HIV‐1 transmission, with rates of about 8% being observed in non‐clinical trial settings. Internationally, the results have led to the development of a variety of perinatal prevention trials that build on the success of the U.S. perinatal prevention trial but use modified strategies that can feasibly be carried out in developing countries.
The testis: the witness of the mating system, the site of mutation and the engine of desire
Authors: Short RV
Published: March 2012

There is now abundant evidence in a wide range of mammalian and non‐mammalian species to show that the relative size of the testis and the morphology of the spermatozoa are infallible predictors of the mating system. Species with the largest testis/body weight ratios and the best spermatozoa have a multi‐male or promiscuous mating system in which sperm competition operates. Judged by these criteria, men were not designed to be promiscuous. There is increasing evidence in humans to show that most spontaneous mutations of the germ line occur in the testis. Because these provide the variability on which natural selection can operate, the testis holds the key to evolution. Genes on the Y chromosome that control male fertility are particularly prone to mutations, perhaps because of the mutagenic metabolites produced by the metabolically active testis. Testicular descent into a scrotum, and cooling by countercurrent heat exchange between the spermatic artery and vein may have evolved as a way of holding the mutation rate in check. The hormones secreted by the testis, which control libido and aggression, ensure that these male mutations are disseminated as widely as possible throughout the population.
Environmental and genetic determinants of neural migration and postmigratory survival*
Authors: Evrard P. , Marret S. , Gressens P.
Published: March 2012

The study of genetic/epigenetic/environmental factors underlies all therapeutic and preventive approaches in fetal, perinatal and paediatric neurology, including rehabilitation (3). In this paper, we selected a few targets of environmental determinants of brain development leading to underlying priorities for protection of the developing brain. Preparation of the neural germinative epithelium has to be protected against noxious pharmacological agents. New tools have been developed to improve early neural teratology, including the whole‐embryo culture method. The neopallial astrocytic precursors have a dual origin. Astrocytes of the white matter and deep neocortical layers derive from transformed radial glial cells, whereas astrocytes of the upper neocortical layers derive from astrocytic precursors that migrate from the late germinative zone after the end of neuronal migration. Among numerous factors able to interfere with these gliogenetic events are the control factors of the lysosomal and autophagic functions, interfering with radial glial cell transformation into astrocytes. All lesions interrupting the migratory corridors of late astroglial migration can produce cytoarchitectonic disturbances of the neocortical supragranular layers, with long‐term consequences. The developing brain is weltering in a complex mixture including newly recognized excitotoxic substances, cytokines and growth factors. These substances are sometimes environmental friends like maternal vasointestinal peptide, which prevents brain intrauterine growth retardation. They are sometimes excellent endogenous friends like neurotrophic excitatory agents in physiological conditions. They become often dangerous killers triggered by environmental signals like hypoxias/ischaemias and toxins produced by intrauterine infections, launching the excitotoxic cascade. In this paper, we reviewed mainly environmental determinants interfering with neural cytogenesis and histogenesis during the embryonic, fetal and neonatal span of early life.
Effect of training and environment on brain morphology and behavior
Authors: Schrott LM
Published: March 2012

Using defined rearing or training paradigms, environmental stimulation has been found to increase brain weight (especially forebrain), cortical thickness, the number of glial cells, the glia to neuron ratio, neuronal cell body and nucleus size, and to alter synaptic profiles by increasing dendritic branching, dendritic spine density and the number of discontinuous synapses. Examples will be given from both animal and human studies that document these profound changes. Controversy exists as to whether enriched environments and/or training can compensate for neural deficits produced earlier in life. Examples will be given from animal studies with induced cortical lesions and prenatal genetic neural anomalies that support a role for environmental manipulations ameliorating earlier central nervous system damage.
Conceptualizing genetic influences on early behavioral development
Authors: Goldsmith HH , Bihun JT
Published: March 2012

The overarching goal of human behavioral genetics is to understand genetic influences on behavior while also considering the complementary influence of the environment. This paper highlights the explicit goals of behavioral genetics, including some that are particularly relevant to the study of human development, and some common misunderstandings concerning the field. Examples are given to illustrate specifically the degree of genetic influence in behaviors representing physical, cognitive and emotional development during infancy using the methodology of twin, adoption and parent‐offspring designs. The effect sizes in the prediction of complex behaviors are typically modest, and thus there is ample room for multiple predictors from different domains. Moreover, there is a fundamental recognition that distal and proximal causes can be different in kind, and that factors that play a role in the origins of behavioral dispositions are different from those that elicit or maintain actual behavior.
Diet and infant behavior
Authors: de Klerk A. , Schulze KF , Kashyap S. , Sahni R. , Fifer W. , Myers M.
Published: March 2012

We studied 142 preterm infants (mean gestation 31 weeks, mean birthweight 1364 g) fed prospectively varied protein and energy intakes. Infants were grouped as either slow or rapid growers based on rate of weight gain. Rapid growers had increased heart rates (166 vs 160 beats/min), respiratory rates (55.7 vs 53.9 bpm), energy expenditure (64.8 vs 61.6 kcal kg−1 day−1), urinary C‐peptide levels (1.59 vs 0.79 ng ml−1) and time in active sleep (78.0 vs 75.2%), and decreased spectral edge frequency in the electroencephalogram (2.96 vs 4.45 Hz) compared to slow growers. We conclude that preterm infants growing at varying rates manifest physiological and behavioral differences, and that these patterns may reflect altered autonomic balance.
Long‐term effects of intrauterine growth retardation
Authors: Kjellmer I. , Liedholm M. , Sultan B. , Wennergren M. , Götborg C. Wallin , Thordstein M.
Published: March 2012

Intrauterine growth retardation (IUGR) was studied both after experimental induction in rats and spontaneously occurring in man. The growth‐retarded rat pups were compared to appropriately grown litter mates with developmental and behavioural tests at 50 and 90 days of age. Female rats exhibited no differences between growth‐retarded and control rats but growth‐retarded male rats had poor performance at 50 but not at 90 days compared to male controls. In the patient study 25 growth‐retarded babies were compared with 21 appropriately grown controls. The growth‐retarded babies had delayed latency periods of the visual evoked potentials at term and 6 weeks later, and at follow‐up (18 months) demonstrated significantly more developmental and behavioural problems than the control group.
Insulin‐like growth factor I gene deletion causing intrauterine growth retardation and severe short stature
Authors: Woods KA , Camacho‐Hübner C. , Barter D. , Clark AJL , Savage MO
Published: March 2012

The first human case of a homozygous molecular defect in the gene encoding insulin‐like growth factor I (IGF‐I) is described. The patient was a 15‐year‐old boy from a consanguineous pedigree who presented with severe intrauterine growth failure, sensorineural deafness and mild mental retardation. Endocrine evaluation of the growth hormone (GH)–IGF‐I axis revealed elevated GH secretion, undetectable serum IGF‐I and normal serum IGF‐binding protein‐3, acid‐labile subunit, and GH‐binding activity. Analysis of the IGF‐I gene revealed a homozygous partial IGF‐I gene deletion involving exons 4 and 5, which encodes a severely truncated mature IGF‐I peptide. This patient demonstrates that complete disruption of the IGF‐I gene in man is compatible with life, and indicates a major role for IGF‐I in human fetal growth. In addition, his neurological abnormalities suggest that IGF‐I may be involved in central nervous system development. □ Insulin‐like growth factor I, growth disorders, intrauterine growth retardation, growth hormone resistance, sensorineural deafness
Hypogonadism and endocrine metabolic disorders in Prader—Willi syndrome
Authors: Müller J.
Published: March 2012

Disturbances of the hypothalamic—pituitary—gonadal axis are reviewed in patients with Prader—Willi syndrome, and a brief account is given of thyroid function, adrenal function and glucose metabolism in such patients. Cryptorchidism, hypoplastic external genitalia and delayed or incomplete pubertal development in most patients with Prader—Willi syndrome suggest dysfunction of the hypothalamic—pituitary—gonadal axis. Decreased levels of gonadotrophins, consistent with hypogonadotrophic hypogonadism, have been found in some patients, whereas others appear to have hypergonadotrophic hypogonadism secondary to cryptorchidism and its treatment. Gonadal function is normal in a small number of patients with the syndrome. Although most clinicians agree that cryptorchidism should be corrected in early childhood, in practice the surgery is often not performed. In addition, most patients do not receive sex hormone replacement therapy. It is therefore suggested that more aggressive endocrine treatment strategies for hypogonadism are warranted in both children and adults with Prader—Willi syndrome. Both thyroid function and adrenal function appear to be normal in most patients, and glucose metabolism is similar to that in normal obese individuals.
Pituitary hormones and immune function
Authors: Berczi I.
Published: March 2012

The pituitary gland plays a key role in the regulation of growth, differentiation and function of all cells in the body, including immunocytes. Immune reactions are generated through the proliferation of antigen‐specific lymphocyte clones. Growth hormone and prolactin are required for the development of mature lymphocytes and for the maintenance of immunocompetence. These hormones enable lymphocytes to respond to antigen, which is delivered as an adherence signal in the context of major histocompatibility surface molecules of antigen‐presenting cells. Numerous other adhesion molecules play a role in the regulation of lymphocyte activation. The activation process is completed by cytokine signalling, after which lymphocyte proliferation, differentiation and functional maturation take place. Interleukins, hormones and growth factors may all function as cytokines. Many lymphocytes exist in the body in a quiescent state, with minimal metabolic activities. These cells are maintained by competence hormones and insulin‐like growth factor I, which are present in the systemic and local environment. Apparently, some steroid hormones, opioid peptides and catecholamines are capable of modulating delivery of the signal from the lymphocyte membrane receptor to the nucleus. Steroid and thyroid hormones control nuclear transcription factors as their receptors, and thus are powerful regulators of lymphocyte signalling at the nuclear level. The bioactive forms of thyroid hormone and of several steroid hormones are generated locally by immunocytes. These important hormonal immunoregulators function both at systemic and local levels. Glucocorticoids are major regulators of cytokine production, and α‐melanocyte‐stimulating hormone functions as a powerful cytokine antagonist. The hormones secreted or regulated by the pituitary gland therefore regulate every level of immune activity, including the competence of lymphocytes to respond to immune/inflammatory stimuli, signal transduction, gene activation, the production and activity of cytokines and other immune effector functions. □ Pituitary hormones, immune function, growth hormone, prolactin, lymphocytes, cytokines, thyroid hormone, glucocorticoids, insulin‐like growth factor I, steroid hormones
Role of B‐cells in growth hormone—immune interactions
Authors: Rapaport RG , Bozzola M.
Published: March 2012

Cells demonstrating cell surface markers for B‐cells tend to be normal in growth hormone (GH)‐deficient children. Treatment with pituitary‐derived or recombinant human GH, however, produces a significant, albeit transient, decrease in the number of these cells both in vitro and in vivo. Receptors for GH have been detected on numerous cells of the immune system, notably B‐cells and monocytes. Recent studies have shown that cells of the immune system are able to produce peptide hormones, such as GH, and studies in the rat (which have yet to be confirmed in humans) suggest that the B‐cell is the cell type most involved in this production. These findings suggest that the B‐cell has a significant role in the bi‐directional communication network between the endocrine and immune systems. □ B‐cells, growth hormone, immune system, lymphocytes
The biology of bone maturation and ageing
Authors: Cox LA
Published: March 2012

The only indicator of development that is available from birth to maturity is skeletal age. This short review discusses how standard bone ages have been developed from assessment of radiographs, and describes the advantages and disadvantages of the 'atlas' approach as developed by Greulich and Pyle, and the bone by bone approach, as developed by Tanner. As the standards currently available are based mainly on historical series of radiographs from particular populations, it is stressed that national standards should be established and updated regularly if bone ages are to be used to assess development. The question of the clinical relevance of using bone age assessments of the hand and wrist to determine the state of maturation of the whole skeleton and, particularly, the growth potential is also discussed. It is concluded that, despite the difficulties of assessing bone age, and the assumptions on which the various methods are based, determination of skeletal development is clinically relevant in that it provides the only means of assessing rates of maturational change throughout the growing period. □ Bone age, skeletal maturation, ageing, development
Intrauterine programming of coronary heart disease and stroke
Authors: Barker DJP
Published: March 2012

We have become accustomed to the idea that the major disorders of adult life, including coronary heart disease, stroke and diabetes, arise from an interaction between influences in our adult lifestyle and a genetically determined susceptibility. Recent research, however, suggests that growth in utero may also play an important role. □ Programming, intrauterine growth, birth weight, undernutrition, coronary heart disease, stroke
Postnatal growth of children born small for gestational age
Authors: Albertsson‐Wikland K. , Karlberg J.
Published: March 2012

A large, population‐based representative study (n = 3656) has shown that the vast majority of healthy, full‐term, singleton infants born small for gestational age (SGA) achieve catch‐up growth during the first 2 years of life. Indeed, most of the increase in height SDS occurs by 2 months of age. Children born SGA who do not show postnatal catch‐up growth and so remain short at 2 years of age, have a higher risk of short stature (< −2 SDS) in later life, with a relative risk at 18 years of age of 5.2 if born light and of 7.1 if born short. □ Small for gestational age, postnatal growth, catch‐up growth, final height, population study
Antenatal therapy for intrauterine growth retardation
Authors: Harding JE , Bauer MK , Kimble RM
Published: March 2012

Currently, there is no effective antenatal therapy for intrauterine growth retardation (IUGR). Although the IUGR fetus is undernourished in utero and there have been many attempts to treat IUGR with nutritional supplements, most studies have been poorly controlled, and there is no evidence to date that nutrient supplements can reverse the process of IUGR once it is established. Nutrient supplementation is also potentially risky and a combination of nutrients is likely to be needed. Alternative approaches to antenatal therapy for IUGR that show promise include fetal growth hormone and insulin‐like growth factor I treatment to improve fetal growth. Fetal and maternal hormone supplements may also prove useful in IUGR by improving placental function and thus fetal substrate supply. Fetal enteral supplementation by the administration of growth factors and/or nutrients into the amniotic fluid may also prove effective and clinically feasible. It seems likely that combinations of these approaches will be required before effective therapy can be devised for the IUGR fetus in utero. □ Amniotic fluid, fetus, growth, growth hormone, growth retardation, insulin‐like growth factor I, nutrition, therapy
Growth hormone treatment of short children born small for gestational age: reappraisal of the rate of bone maturation over 2 years and metanalysis of height gain over 4 years
Authors: de Zegher F. , Butenandt O. , Chatelain P. , Albertsson‐Wikland K. , Jonsson B. , Löfström A. , Chaussain J‐L
Published: March 2012

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch‐up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. A previous metanalysis of four trials revealed that GH treatment over a period of 2 years induced a dose‐dependent acceleration of linear growth and, to a lesser extent, of the rate of bone maturation in short, prepubertal children born SGA. The rate of bone maturation and the change in height SDS for bone age from the previous 2‐year metanalysis have been re‐analysed according to chronological age (two prepubertal age groups: group A, 3.0–5.9 years old; group B, 6.0–8.9 years old). The rate of bone maturation was slower in younger than in older prepubertal children; this difference was more marked in children receiving high‐dose (0.2 or 0.3 IU/kg/day) GH treatment (p ≤ 0.01). Accordingly, the change in height SDS for bone age was increased by high‐dose GH treatment in both age groups (p ≤ 0.01), and was more pronounced in younger than in older children (1.45 ± 0.28 versus 0.63 ± 0.20; p ≤ 0.01). Height SDS data from 100 short, prepubertal children born SGA have been analysed over 4 years. The change in height SDS appeared to be related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2 IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous). After 4 years of treatment, the increase in height SDS for the continuous and discontinuous treatment schedules was similar, being 1.42 ± 0.10 SDS and 1.58 ± 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment (discontinuous). After 3 years, the increase in height SDS with the continuous and discontinuous treatment schedules was similar, being 2.01 ± 0.18 SDS and 2.22 ± 0.16 SDS, respectively. GH administration was well tolerated in all treatment groups. In conclusion, the rate of bone maturation in short, prepubertal children born SGA treated with GH appeared to depend not only on the dose of GH, but also on the age of the child. GH treatment resulted in a prolonged increase in height SDS, the magnitude of the rise being dependent on the average GH dose rather than on the continuous or discontinuous mode of GH administration. □ Growth hormone, small for gestational age, catch‐up growth, short stature, rate of bone maturation, height, prepuberty