Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

Support for the hypoxia theory in the pathogenesis of infantile haemangioma.

BACKGROUND: The pathogenesis of infantile haemangioma (IH) is unknown. Several mechanisms have been proposed, including hypoxia, which triggers upregulation and stabilization of hypoxia-inducible factor (HIF)1α. HIF1α stimulates downstream transcription of target genes that enhance angiogenesis. AIM: To identify possible involvement of hypoxia in the pathogenesis of IH, as hypoxia signalling constitutes a potential therapeutic target. METHODS: IH tissue samples collected during the period 1991-2011 (preserved in paraffin wax) were immunohistochemically analysed for HIF1α and the known HIF1α targets: BCL2/adenovirus E1B kD-interacting protein family member 3 (BNIP3), carbon anhydrase (CA)-IX, glucose transporter (GLUT)-1, phosphorylated protein kinase B (pAKT), phosphorylated S6 protein (pS6) and vascular endothelial growth factor (VEGF). Four observers independently assessed the findings. RESULTS: Of the 10 IH samples, 2 appeared to be in the growth phase. In all samples, GLUT-1, BNIP3, pAKT and VEGF were positive, CA-IX was weakly positive, and HIF1α was negative. pS6 was positive in 9/10 cases and negative in 1/10. CONCLUSIONS: Several factors implicated in hypoxia-induced angiogenesis may be involved in IH development. However, the small sample size and retrospective approach of the study preclude definitive conclusions. Prospective studies are needed to conclusively determine which of the factors involved in the (hypoxia) cascade are required for an IH to grow, and could thus be a possible target of drugs for IH treatment.

Use of highly active antiretroviral therapy is associated with lower prevalence of anal intraepithelial neoplastic lesions and lower prevalence of human papillomavirus in HIV-infected men who have sex with men.

BACKGROUND: The incidence of anal intraepithelial neoplasia (AIN) and anal cancer is increased in HIV-positive men who have sex with men (MSM). Persistent high-risk human papillomavirus (HPV) infection is an important etiologic agent. METHODS: In this study, a group of 250 HIV-positive MSM was included to determine the prevalence of AIN and to investigate the role of highly active antiretroviral therapy (HAART), high-risk HPV, and other risk factors possibly associated with this prevalence. RESULTS: Among patients included, 108 (43.2%) had lesions suspicious for AIN. Histologic analyses showed AIN 1 in 24 patients (22.2%), AIN 2 in 6 patients (5.6%), and AIN 3 in 10 patients (9.3%). In multivariable analyses, the use of HAART was associated with the absence of AIN (P = 0.045). In MSM without HAART, HPV infection was detected significantly more often compared with those who used HAART (P = 0.010). AIN was associated with HPV types 16 and 6. CONCLUSIONS: In this cross-sectional study in 250 HIV-positive MSM, the use of HAART was associated with lower prevalence of AIN and a significantly lower prevalence of HPV. This association between the prevalence of AIN and the absence of HAART may contribute to the current debate on when to start HAART in HIV-infected individuals.

Alterations in leucocyte subsets and histomorphology in normal-appearing perilesional skin and early and chronic hidradenitis suppurativa lesions.

BACKGROUND: Current insight into the histopathological course of events during disease progression in hidradenitis suppurativa (HS) is fragmentary. OBJECTIVES: To identify histological alterations and leucocyte subsets in normal-appearing perilesional skin, and early and chronic HS lesions. METHODS: In this observational study we examined eight perilesional skin samples, and six early and 10 chronic prototypic HS lesions, as well as skin samples from four healthy donors using in situ immunostaining. RESULTS: Perilesional skin showed mild psoriasiform hyperplasia and follicular plugging as well as a low-grade influx of tryptase-positive mast cells, CD3+ T cells, CD138+ plasma cells and factor XIIIa+ dendritic cells. In early HS lesions, neutrophilic abscess formation and influx of mainly macrophages, monocytes and dendritic cells predominated. In chronic disease, the infiltrate expanded with markedly increased frequencies of CD20+ and CD79a+ B cells and CD138+ plasma cells. As in early lesions, free keratin fibres were detected in the dermis and within giant cells. Single detached keratinocytes and strands of follicular epithelium were observed in the dermis, the latter frequently expressing Ki67, indicative of active proliferation. CONCLUSIONS: Psoriasiform hyperplasia, follicular plugging and low-grade leucocytic infiltration are already present in normal-appearing perilesional skin. Keratin fibres in the dermis are associated with clinical disease. Early lesions are characterized by neutrophilic abscess formation and influx of mainly histiocytes, and chronic lesions mainly by expansion of B cells and plasma cells in 'pseudo' follicles. Proliferating strands of follicular epithelium may initiate fistula formation. Mast cells are increased in all stages of HS including perilesional skin.

Cellular applications of 31P and 13C nuclear magnetic resonance.

High-resolution nuclear magnetic resonance (NMR) studies of cells and purified mitochondria are discussed to show the kind of information that can be obtained in vivo. In suspensions of Escherichia coli both phosphorus-31 and carbon-13 NMR studies of glycolysis and bioenergetics are presented. In rat liver cells the pathways of gluconeogenesis from carbon-13-labeled glycerol are followed by carbon-13 NMR. In the intact liver cells cytosolic and mitochondrial pH's were separately measured by phosphorus-31 NMR. In purified mitochondria the internal and external concentrations of inorganic phosphate, adenosine diphosphate, and adenosine triphosphate were determined by phosphorus-31 NMR while the pH difference across the membrane was measured simultaneously.

Unusual late nodular presentation of secondary syphilis.

A 20-year-old man presented with a five-week history of an eruption of papules and nodules disseminated over his body and face. We propose that this patient has a late form of secondary syphilis with a nodular, granulomatous inflammation in urgent need of treatment. Otherwise late irreversible sequelae could develop and unwanted possible further sexual transmission could take place.

An itchy holiday.

A 33-year-old Dutch woman developed itchy skin lesions during a beach holiday in Thailand. She was treated for various diagnoses, without success. Finally she was successfully treated for a clinically suspected hookwormrelated folliculitis. A brief overview of hookworm-related folliculitis is given.

[Adenoid cystic carcinoma of the upper eyelid]. / Adenoid-zystisches Karzinom des Oberlids.

Adenoid cystic carcinoma (ACC) is a rare epithelial malignancy, which tends to grow slowly. ACC is an intractable neoplasm due to its ability to invade perineural spaces. Local recurrence after excision is not unusual. ACC most commonly arises in the lacrimal gland. Very rarely, ACC originates from accessory lacrimal gland tissue. Here, we present a patient with a large ACC of the central upper eyelid, which had been misdiagnosed and treated as a chalazion without histological examination. Its origin most likely is an accessory lacrimal gland.

Kinetics and pH-dependence of glycine-proton symport in Saccharomyces cerevisiae.

Interactions between intracellular pH (pHi) and H+-coupled transmembrane transport of glycine have been studied by means of 31P-NMR, using both aerobic and 'energy starved' cells of the yeast Saccharomyces cerevisiae. The general features of glycine transport in the yeast strain used (NCYC 239) are similar to those already reported for Saccharomyces carlsbergensis and S. cerevisiae, there being two kinetically distinct glycine uptake systems, with pH-independent K1/2 values near 14 and 0.4mM, respectively, but pH-dependent maximal velocities. Glycine transport itself has no measurable effect on pHi in aerobic cells, and only a marginal effect in energy-starved cells, but changes of pHi, imposed by extracellular addition of butyric acid, strongly influence glycine transport. Indeed, the dependence of glycine influx (in energy-starved cells) upon cytoplasmic H+ concentration appears to be third order, showing Hill slopes of 2.7-3.0. A crucial kinetic role for cytoplasmic pH in glycine transport is further indicated by a proportionality between the decline of flux and the decline of pHi produced by various metabolic inhibitors and uncouplers. Extracellular pH (pHo), by contrast, has only a weak effect on glycine influx, showing a Hill slope of 0.5. The major observations can be accommodated by a simple cyclic carrier scheme, in which 2 or more protons are transported along with glycine, but only one extracellular proton binding site dissociates in the testing range, with a pK near 5.5. The model requires a finite membrane potential, which must be somewhat sensitive to both pHi and pHo, and accommodates the discrepancy between measured net proton flux (one per glycine) and the kinetically required proton flux (two or more per glycine) by shunting through other proton-conducting pathways in the yeast membrane.

Mast cell distribution in normal adult skin.

AIMS: To investigate mast cell distribution in normal adult skin to provide a reference range for comparison with mastocytosis. METHODS: Mast cells (MCs) were counted in uninvolved skin adjacent to basal cell carcinomas and other dermatological disorders in adults. RESULTS: There was an uneven distribution of MCs in different body sites using the anti-tryptase monoclonal antibody technique. Numbers of MCs on the trunk, upper arm, and upper leg were similar, but were significantly different from those found on the lower leg and forearm. Two distinct groups were formed--proximal and distal. There were 77.0 MCs/mm2 at proximal body sites and 108.2 MCs/mm2 at distal sites. Adjusted for the adjacent diagnosis and age, this difference was consistent. The numbers of MCs in uninvolved skin adjacent to basal cell carcinomas and other dermatological disorders were not different from those in the control group. Differences in the numbers of MCs between the distal and the proximal body sites must be considered when MCs are counted for a reliable diagnosis of mastocytosis. A pilot study in patients with mastocytosis underlined the variation in the numbers of MCs in mastocytosis and normal skin, but showed a considerable overlap. The observed numbers of MCs in adults cannot be extrapolated to children. CONCLUSIONS: MC numbers varied significantly between proximal and distal body sites and these differences must be considered when MCs are counted for a reliable diagnosis of mastocytosis. There was a considerable overlap between the numbers of MCs in mastocytosis and normal skin.

Expression and prognostic value of Wilms' tumor 1 and early growth response 1 proteins in nephroblastoma.

Wilms' tumor is one of the most common solid tumors of children. The protein product of the tumor-suppressor gene, Wilms' tumor 1 (WT-1), binds to the same DNA sequences as the protein product of the early growth response 1 (EGR-1) gene. There is experimental evidence that EGR-1 is involved in controlling cell growth. The expression of both genes in Wilms' tumor was studied by others, mainly at the mRNA level. The present study evaluates the prognostic value of WT-1 and EGR-1 in 61 Wilms' tumors of chemotherapeutically treated patients at the protein level, using an immunohistochemical approach. WT-1 was expressed in normal kidney tissues and in the blastemal and epithelial component of Wilms' tumor, whereas stromal tissue was negative. EGR-1 was expressed in normal kidney tissues and in the three main cell types of Wilms' tumor. In 59 and 56% of Wilms' tumor, the blastemal cells stained for WT-1 and EGR-1, respectively. The blastemal expression of WT-1 and EGR-1 and the epithelial expression of WT-1 were statistically significantly correlated with clinical stage. WT-1 immunoreactivity correlated with EGR-1 expression. Univariate analysis showed that blastemal WT-1 and EGR-1 expression were indicative for clinical progression and tumor-specific survival, whereas epithelial staining was of no prognostic value. Multivariate analysis showed that blastemal WT-1 expression is an independent prognostic marker for clinical progression other than stage. We conclude that a relationship exists between WT-1 and EGR-1 expression in clinical nephroblastomas. Blastemal WT-1 and EGR-1 expression is related to prognosis.

[Anorectal malignancies and dysplasia in HIV-positive men who have sex with men]. / Anuscarcinoom en voorstadia hiervan bij HIV-positieve mannen die seks hebben met mannen.

Since the HIV epidemic, the incidence ofanorectal (pre)malignancies in men who have sex with men (MSM) is increasing. The incidence is likely to increase further in the coming years, given that HIV-positive MSM are living longer thanks to powerful antiretroviral treatment. Persistent human papillomavirus (HPV) infection is a major risk factor for the development of anal (pre)malignancies. Less is known about the natural history of anal intraepithelial neoplasia (AIN). Screening in HIV-positive and HIV-negative MSM for anorectal malignancies or dysplasia is cost-effective if the incidence is sufficiently high. Treatment options range from watchful waiting for asymptomatic grade-1 AIN to excision or radio(chemo)therapy for anorectal carcinoma. HPV vaccines are in development. Especially in HIV-positive MSM with anorectal complaints or genital warts in their medical history, one should consider these malignancies.

Ontogeny of iodothyronine deiodinases in human liver.

The role of the deiodinases D1, D2, and D3 in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in animals but little is known about the ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently healthy adult tissue transplant donors, and in liver homogenates from 2 fetuses (20 weeks gestation), 5 preterm infants (27-32 weeks gestation), and 13 term infants who survived up to 39 weeks postnatally. D1 activity was determined using 1 microM [3',5'-125I]rT3 as substrate and 10 mM dithiothreitol (DTT) as cofactor, D2 activity using 1 nM [3',5'-125I]T4 and 25 mM DTT in the presence of 1 mM 6-propyl-2-thiouracil (to block D1 activity) and 1 microM T3 (to block D3 activity), and D3 activity using 10 nM [3,5-125I]T3 and 50 mM DTT, by quantitation of the release of 125I. The assays were validated by high performance liquid chromatography of the products, and kinetic analysis [Michaelis-Menten constant (Km) of rT3 for D1: 0.5 microM; Km of T3 for D3: 2 nM]. In liver homogenates, D1 activity was not correlated with age, whereas D3 activity showed a strong negative correlation with age (r -0.84), with high D3 activities in preterm infants and (except in 1 infant of 35 weeks) absent D3 activity in full-term infants. In microsomes, D1 activities amounted to 4.3-60 pmol/min/mg protein in fetal livers and to 170-313 pmol/min/mg protein in adult livers, whereas microsomal D3 activities were 0.15-1.45 pmol/min/mg protein in fetuses and <0.1 pmol/min/mg protein in all but one adult. In the latter sample, D3 activity amounted to 0.36 pmol/min/mg protein. D2 activity was negligible in both fetal and adult livers. These findings indicate high D1 and D3 activities in fetal human liver, and high D1 and mostly absent D3 activities in adult human liver. Therefore, the low serum T3 levels in the human fetus appear to be caused by high hepatic (and placental) D3 activity rather than caused by low hepatic D1 activity. The occasional expression of D3 in adult human liver is intriguing and deserves further investigation.

Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy.

We determined cerebral intracellular pH in living rabbits and rats under physiologic conditions, using phosphorus NMR spectroscopy and new titration curves thought to be appropriate for brain. Mean values for the two species were, respectively, 7.14 +/- 0.04 (SD) and 7.13 +/- 0.03. These are toward the alkaline end of the range of values obtained by other methods, as values reported by other NMR workers also tend to be.

In vivo monitoring of fructose metabolism in the human liver by means of 31P magnetic resonance spectroscopy.

It has been shown that fructose metabolism in the human liver can be monitored quantitatively by means of 1H image-guided 31P MRS, implemented on a clinical MR imaging system equipped with surface coils and with appropriate data processing software. Temporal resolution of the 31P MRS measurements is of the order of 2 min.

Prenatal lethality of a homozygous null mutation in the human glucocerebrosidase gene.

The complete spectrum of clinical phenotypes resulting from glucocerebrosidase deficiency continues to evolve. While most patients with Gaucher disease have residual glucocerebrosidase activity, we describe a fetus with severe prenatal lethal type 2 (acute neuronopathic) Gaucher disease lacking glucocerebrosidase activity. This 22-week fetus was the result of a first cousin marriage and had hydrops, external abnormalities, hepatosplenomegaly, and Gaucher cells in several organs. Fetal fibroblast DNA was screened for common Gaucher mutations, none of which was detected. Southern blot analysis using the restriction enzymes SstII and SspI ruled out a fusion gene, deletion, or duplication of either allele, and quantitative studies of SspI digested genomic DNA indicated that both alleles were present. Northern blot analysis of total RNA from fetal fibroblasts demonstrated no detectable transcription, although RT-PCR successfully amplified several exons, suggesting the presence of a very unstable mRNA. Direct PCR sequencing of all exons demonstrated a homozygous frameshift mutation (deletion of a C) on codon 139 in exon 5, thereby introducing a premature termination codon in exon 6. The absence of glucocerebrosidase protein was confirmed by Western analysis. This unique case confirms the essential role of glucocerebrosidase in human development and, like the null allele Gaucher mouse, demonstrates the lethality of a homozygous null mutation. The presence of this novel mutation and the resulting unstable mRNA accounts for the severity of the phenotype observed in this fetus, and contributes to the understanding of genotype/phenotype correlation in Gaucher disease.

Prenatal diagnosis of cystic kidney disease with ventriculomegaly: a report of six cases in two related sibships.

In 2 consanguineous relationships, a Cape Verdian man fathered six fetuses (5 male) with fetal ventriculomegaly and echodense fetal kidneys as visualized by ultrasonography between 16 and 32 weeks. During prenatal monitoring, an increased alpha fetoprotein level and abnormal acetylcholinesterase were detected at amniocentesis in 5 of 6 affected fetuses. Chromosomes were normal. Five pregnancies resulted in elective termination; one child was still-born prematurely. Hydrocephalus and cystic disease of the (renal) cortico medullary areas were found. One fetus had polydactyly. The differential diagnosis and prenatal diagnosis of this presumably autosomal recessive syndrome are discussed.

Recurrent digital fibroma, focal dermal hypoplasia, and limb malformations.

Recurrent digital fibroma of infancy generally is considered a sporadic tumor of childhood. We describe the case of a mother with recurrent digital fibroma at a young age who gave birth to a daughter with focal dermal hypoplasia, coloboma of the iris and eyelids, anal atresia, and extensive limb malformations. When the infant was 3 months old, fibromas started to appear at the fingertips. The cases of three additional patients are described, with a similar combination of multiple digital fibromas, pigmented marks on the temporal region, and limb malformations. One of these patients has consanguineous parents. The clinical findings overlap partially with Gorlin-Goltz syndrome, which has been renamed by some authors "microphthalmia with linear skin defects" (MLS). Since the skin signs are clearly different, however-more like those of Setleis syndrome ("forceps mark" temporal dysplasia)-the patients described here seem to have a new combination of congenital malformations. Deletion of distal Xp, known to occur in some MLS patients, was not detected using cosmids in fluorescence in situ hybridization. This pattern of digital fibroma with congenital malformations seems to represent a new syndrome.

Unexpected life-threatening complications in Kabuki syndrome.

Kabuki syndrome is a rare multiple congenital anomalies/mental retardation syndrome comprising a distinct facial appearance and fetal fingertip pads. We observed two patients with Kabuki syndrome and describe unusual life-threatening complications, including stenosis of the central airways (not previously reported), extrahepatic biliary atresia, and congenital diaphragmatic hernia.