Impaired bone and muscle development in young people treated with antiepileptic drugs.

OBJECTIVE: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs. METHODS: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details. RESULTS: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (Fmax total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures. SIGNIFICANCE: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes.

Intravenous glucagon in a deliberate insulin overdose in an adolescent with type 1 diabetes mellitus.

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.

Where should we measure waist circumference in clinically overweight and obese youth?

AIMS: Waist circumference (WC) measurement is a useful tool in the assessment of overweight/obese individuals, but standard measures may miss an apron of 'overhanging' fat (termed 'panniculus'). The objective of this study was to assess whether, in clinically overweight/obese youth, 'pannicular' WC better correlates with fat mass than a standard WC measurement. METHODS: Standard and pannicular WC, alongside body composition (BC) measures, were collected from 181 consultations on 127 overweight and obese children/adolescents (52% male; mean (standard deviation) age 12.5 (3.4) years). Correlation coefficients describe associations between WC and measures of BC, and between ΔWC and ΔBC, while linear regression models assessed which of the WC measures explained more of the variability in BC and ΔBC over time. RESULTS: Standard and pannicular WC were highly correlated (r = 0.95). Correlation coefficients with measures of BC were generally greater for pannicular than standard WC, with greatest correlations seen for whole body (r = 0.94 vs. 0.85, respectively) and truncal (r = 0.86 vs. 0.77) fat mass. Furthermore, pannicular and Δpannicular WC explained more variability in truncal fat and Δtruncal fat than the standard measure of WC. CONCLUSIONS: These data show that pannicular, rather than standard, WC measurements better correlate with absolute measures of fat mass, and their change over time, in clinically overweight/obese youth.

Effects of fluctuating glucose levels on neuronal cells in vitro.

There is increasing evidence for glucose fluctuation playing a role in the damaging effects of diabetes on various organs, including the brain. We aimed to study the effects of glycaemic variation (GV) upon mitochondrial activity using an in vitro human neuronal model. The metabolic disturbance of GV in neuronal cells, was mimicked via exposure of neuroblastoma cells SH-SY5Y to constant glucose or fluctuating (i.e. 6 h cycles) for 24 and 48 h. Mitochondrial dehydrogenase activity was determined via MTT assay. Cell mitochondrial activity (MTT) was moderately decreased in constant high glucose, but markedly decreased following 24 and 48 h of cyclical glucose fluctuations. Glucose transport determined via 2-deoxy-D-[1-(14)C] glucose uptake was regulated in an exaggerated manner in response to glucose variance, accompanied by modest changes in GLUT 1 mRNA abundance. Osmotic components of these glucose effects were investigated in the presence of the osmotic-mimics mannitol and L: -glucose. Both treatments showed that fluctuating osmolality did not result in a significant change in mitochondrial activity and had no effects on (14)Cglucose uptake, suggesting that adverse effects on mitochondrial function were specifically related to metabolically active glucose fluctuations. Apoptosis gene expression showed that both intrinsic and extrinsic apoptotic pathways were modulated by glucose variance, with two major response clusters corresponding to (i) glucose stress-modulated genes, (ii) glucose mediated osmotic stress-modulated genes. Gene clustering analysis by STRING showed that most of the glucose stress-modulated genes were components of the intrinsic/mitochondrial apoptotic pathway including Bcl-2, Caspases and apoptosis executors. On the other hand the glucose mediated osmotic stress-modulated genes were mostly within the extrinsic apoptotic pathway, including TNF receptor and their ligands and adaptors/activators/initiators of apoptosis. Fluctuating glucose levels have a greater adverse effect on neuronal cell energy regulation mechanisms than either sustained high or low glucose levels.

An in vitro paradigm for diabetic cerebral oedema and its therapy: a critical role for taurine and water channels.

The pathophysiology of cerebral oedema (CE) in diabetic ketoacidosis (DKA) remains enigmatic. We investigated the role of the idiogenic osmol taurine and aquaporin channels in an in vitro model, the SH-SY5Y neuroblastoma cell line, by sequentially mimicking DKA-like hyperglycemia/hypertonicity and hypotonic fluid therapy. Exposure to DKA-like hyperosmolarity led to shrinkage, while hypotonic fluid exposure led to cell swelling and impaired viability. Low sodium compensated in part for elevated glucose, pointing to a critical role for overall osmolality. Taurine, was synthesized and retained intracellularly during DKA-like hypertonicity, and released during hypotonicity, in part mitigating neuronal swelling. Metabolic labeling showed that the rate of taurine release was inadequate to fully prevent neuronal swelling during hypotonic fluid therapy following DKA-like hypertonicity. Under these conditions, Aquaporin4 & 9 channels were respectively down and up-regulated. Our study provides further novel insights into molecular mechanisms contributing to CE in DKA and its therapy.

Overgrowth syndromes.

PURPOSE OF REVIEW: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings. RECENT FINDINGS: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes. SUMMARY: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.

IGFBP-2 at the interface of growth and metabolism--implications for childhood obesity.

The growth hormone/insulin-like growth factor-I (IGF-I) axis is at the centre of normal human childhood growth. Six well characterised binding proteins (IGFBP-1 to IGFBP-6) act as general carriers of IGF-I, but they also modulate IGF-I bioavailability and activity in a tissue-specific, and developmentally appropriate, manner. Recent findings also point to several binding proteins possessing specific 'lGF-independent' actions and, in particular, there is now substantial evidence linking IGFBP-2 with nutritional status and insulin sensitivity. IGFBP-2 concentrations are reduced in obesity, and further reductions are seen in those with Type 2 diabetes. As IGFBP-2 is the major IGFBP expressed in infancy, and is also the predominant IGFBP produced from adipocytes, it is ideally positioned to act as a keystone between nutrition, growth and metabolism. Childhood obesity is associated with an increased risk of long-term morbidity and mortality, but the factors that determine which obese children will develop these long-term complications are not fully understood. IGFBP-2 may be integrally involved in the molecular processes that govern the development of obesity and subsequent weight-related disease. Within this manuscript, we explore the associations between IGFBP-2 and obesity with a particular emphasis on how an increased understanding of the role of IGFBP-2 in metabolism may lead to improvements in the prevention and treatment of childhood obesity.

Neuropsychological profiles of young people with type 1 diabetes 12 yr after disease onset.

BACKGROUND: Lowered neuropsychological performance is evident in youth with type 1 diabetes, although evidence for associations with specific illness variables is inconsistent. This study examined the neuropsychological profiles of a cohort of youth with type 1 diabetes studied prospectively from diagnosis 12 yr previously. METHODS: A total of 106 youth with type 1 diabetes and 75 healthy controls participated. There were no significant group differences on Full-scale IQ assessed on study entry 12 yr previously, current socioeconomic status, gender distribution, or age. Neuropsychological tests assessed eight cognitive domains: verbal abilities, perceptual reasoning, new learning, working memory, non-verbal processing speed, mental efficiency, divided attention, and sustained attention. Episodes of serious hypoglycemia and HbA(1c) levels were recorded from diagnosis. RESULTS: Youth with type 1 diabetes performed more poorly than controls on working memory (p < .05). Early onset diabetes was related to poorer sustained (p < .001) and divided attention (p = .001), new learning, and mental efficiency (both p < .05). Hypoglycemia was found to adversely effect verbal abilities, working memory, and non-verbal processing speed (all p < .05). Poorer working memory was associated with hyperglycemia (p < .05). Youth with any combination of two or three illness risk factors (i.e., early onset diabetes, hypo-, hyperglycemia), performed more poorly than controls and youth with no or one risk on verbal abilities, working memory, and mental efficiency. CONCLUSIONS: This study documents poorer neuropsychological performance and its association with illness risk factors in youth with type 1 diabetes. Findings suggest that early disease onset and hypoglycemia impact on the developing central nervous system, with hyperglycemia playing a lesser role.

An observational study of type 2 diabetes within a large Australian tertiary hospital pediatric diabetes service.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is emerging as a significant clinical problem within the pediatric population. OBJECTIVE: The objective of this study was to identify patients with T2DM in a large tertiary hospital diabetes service and examine aspects relating to clinical course and management. METHODS: An initial audit of our diabetes service (over 6 yr) was followed by a 2-yr period of prospective case ascertainment to identify patients with T2DM. Comprehensive data collection was then undertaken in these individuals. RESULTS: Within our service (n = 1574), 33 young people with T2DM were identified. Significant levels of co-morbidity were evident - dyslipidaemia (56%), microalbuminuria (45%), hypertension (30%) and abnormal retinal findings (25%). Hypertension was more likely in those with greater initial and follow-up body mass index (BMI) [mean (SD) BMI: 36.3 (5.0) vs. 28.0 (6.3) kg/m(2) , p = 0.001, and 36.8 (5.3) vs. 28.5 (7.8) kg/m(2) , p = 0.007, respectively] and BMI standard deviation score (SDS) [mean (SD) BMI SDS: 2.34 (0.30) vs. 1.72 (0.66), p = 0.001, and 2.26 (0.31) vs. 1.38 (0.87), p < 0.001, respectively], whereas abnormal retinal findings were seen in those with higher HbA1c values at last appointment [geometric mean (range) 10.9 (8.4-13.6) vs. 7.4 (5.6-12.5)%, p = 0.01) and those with greater increases in HbA1c over time (+4.1 (3.1) vs. +0.2 (1.9)%, p = 0.009). Of the 33,9 (27%) were lost to follow-up. CONCLUSIONS: At present, T2DM in youth remains a low burden on our services. Patients with this diagnosis, however, have significant problems that present a major challenge to the development of effective management strategies.

New directions in childhood obesity research: how a comprehensive biorepository will allow better prediction of outcomes.

BACKGROUND: Childhood obesity is associated with the early development of diseases such as type 2 diabetes and cardiovascular disease. Unfortunately, to date, traditional methods of research have failed to identify effective prevention and treatment strategies, and large numbers of children and adolescents continue to be at high risk of developing weight-related disease. AIM: To establish a unique 'biorepository' of data and biological samples from overweight and obese children, in order to investigate the complex 'gene × environment' interactions that govern disease risk. METHODS: The 'Childhood Overweight BioRepository of Australia' collects baseline environmental, clinical and anthropometric data, alongside storage of blood samples for genetic, metabolic and hormonal profiles. Opportunities for longitudinal data collection have also been incorporated into the study design. National and international harmonization of data and sample collection will achieve required statistical power. RESULTS: Ethical approval in the parent site has been obtained and early data indicate a high response rate among eligible participants (71%) with a high level of compliance for comprehensive data collection (range 56% to 97% for individual study components). Multi-site ethical approval is now underway. CONCLUSIONS: In time, it is anticipated that this comprehensive approach to data collection will allow early identification of individuals most susceptible to disease, as well as facilitating refinement of prevention and treatment programs.

Type 1 diabetes--still the commonest form of diabetes in children.

Obesity is rife within the community, and associated conditions such as type 2 diabetes and cardiovascular disease threaten the future health of our children. While type 2 diabetes has been the focus of much media attention, type 1 diabetes mellitus remains the commonest form of newly diagnosed diabetes in childhood. This case study acts to remind practitioners that all young people (even those with established obesity) who present with symptoms, and/or biochemical derangements compatible with diabetes, should be managed acutely in order to avoid a delayed diagnosis of type 1 diabetes.

Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems.

GH and IGF-I and -II were first identified by their endocrine activity. Specifically, IGF-I was found to mediate the linear growth-promoting actions of GH. It is now evident that these two growth factor systems also exert widespread activity throughout the body and that their actions are not always interconnected. The literature highlights the importance of the GH and IGF systems in normal skin homeostasis, including dermal/epidermal cross-talk. GH activity, sometimes mediated via IGF-I, is primarily evident in the dermis, particularly affecting collagen synthesis. In contrast, IGF action is an important feature of the dermal and epidermal compartments, predominantly enhancing cell proliferation, survival, and migration. The locally expressed IGF binding proteins play significant and complex roles, primarily via modulation of IGF actions. Disturbances in GH and IGF signaling pathways are implicated in the pathophysiology of several skin perturbations, particularly those exhibiting epidermal hyperplasia (e.g., psoriasis, carcinomas). Additionally, many studies emphasize the potential use of both growth factors in the treatment of skin wounds; for example, burn patients. This overview concerns the role and mechanisms of action of the GH and IGF systems in skin and maintenance of epidermal integrity in both health and disease.

Adolescent exposure to high-dose estrogen and subsequent effects on lactation.

Treatment with high-dose estrogens has been used to reduce the adult height of tall girls for many years. Short-term side effects on the breast have been reported but there have been no studies to investigate whether there are long-term effects on lactation. This retrospective cohort study of 371 treated and 409 untreated women asked about breastfeeding history. After adjusting for maternal age at first live-birth, treated women (4.4%) were no more likely than untreated women (4.1%) to not commence breastfeeding (RR 1.13, 95% CI 0.50-2.52). After adjusting for age, there was no significant difference in the average duration of breastfeeding between treated (median 41.1 weeks) and untreated women (median 43.3 weeks) (p=0.77) for all live-births. Treated women were not significantly more likely to report physiological reasons for stopping breastfeeding than untreated women. Women treated with high-dose estrogens during adolescence appeared to be no different to untreated women in their ability to lactate.

Childhood obesity.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Expression of the IGF system in normal and diabetic transgenic (mRen-2)27 rat eye.

PURPOSE: In the present study, a recently described model of diabetic eye disease was used to investigate the distribution of the insulin-like growth factor (IGF) system in the eyes of transgenic (mRen-2)27 rats (exhibiting hypertension and elevated serum and ocular renin levels) with streptozotocin-induced diabetes. METHODS: Female transgenic (mRen-2)27 rats were randomized to receive either streptozotocin (diabetic) or citrate buffer (control). After 10 months, the rats were killed and the eyes fixed and embedded in paraffin. In situ hybridization (ISH) was used to document the cellular distribution of mRNAs for components of the IGF system (IGF-I, IGF-I receptor [IGFIR] and IGF binding proteins [IGFBP]1 to -6) in the eyes. RESULTS: In nondiabetic rats, mRNA for IGFBP-1, -5, and -6; IGF-I; and IGFIR were detected in the retina. In addition, IGF-I mRNA was present in the cornea, IGFBP-1 mRNA was observed in the cornea and iris, and IGFBP-5 and -6 mRNAs were identified in the ciliary body, iris, and cornea. mRNAs for IGFBP-2, -3, and -4 were not found in the eyes. In diabetic rats, reduced levels of IGFBP-6 mRNA were detectable, whereas levels of IGFBP-5 mRNA were increased in the inner and outer retina, rods and cones, iris, cornea, and ciliary body. Other components of the IGF system in the eye were unchanged with diabetes. CONCLUSIONS: In the diabetic (mRen-2)27 rat, IGFBP-6 is downregulated and IGFBP-5 is upregulated by induction of diabetes. Because these IGFBPs may respectively have IGF-enhancing and IGF-inhibitory effects, these findings suggest a possible net IGF-enhancing effect induced by diabetes, providing further evidence for a role of the IGF system in the development of diabetic retinopathy.

Child and adolescent growth disorders--an overview.

BACKGROUND: While many children presenting with apparent disorders of growth will be short or tall children growing normally, it is important to identify those children who have an underlying pathological cause. Parental expectation and anxiety will often accompany growth issues and this needs to be addressed. OBJECTIVE: The article aims to assist the clinician in distinguishing pathological short stature from normal variants, and to guide in the management of normal variants and common pathologies. DISCUSSION: Pathological short stature can be distinguished from normal variants by careful history and examination followed by accurate assessment of the growth parameters of height, weight, body proportions and growth velocity, and judicious use of investigations. Growth is a dynamic process that requires multiple measurements over time. If the patient has a nonpathological cause of short stature, explanation and reassurance are critical--for both the parents and child--to feel supported and comfortable with their height outcome.

Risk factors for decline in IQ in youth with type 1 diabetes over the 12 years from diagnosis/illness onset.

OBJECTIVE: This study examined illness-related change in intelligence quotient (IQ) in a cohort of youth with type 1 diabetes studied prospectively from disease onset in childhood to follow-up 12 years later in late adolescence/early adulthood. RESEARCH DESIGN AND METHODS: Participants included type 1 diabetes patients (n = 95; mean age at follow-up 21.3 years) and healthy control participants (HCs; n = 67; mean age at follow-up 21.0 years) from a cohort followed prospectively. Measures included Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children-Revised, and Wechsler Abbreviated Scale of Intelligence and prospective collection of data on metabolic control history. RESULTS: Young people with type 1 diabetes showed greater decline in verbal IQ (VIQ) and full-scale IQ (FSIQ), but not performance IQ (PIQ), than HCs. Within the diabetes group, a younger age at diabetes onset was associated with a decline in PIQ and FSIQ (P ≤ 0.001). A history of hypoglycemic seizures was associated with a decline in VIQ (P = 0.002). Long-term metabolic control was not associated with changes in IQ. Interaction terms were not significant, suggesting no moderating effect of one diabetes-related variable over another. CONCLUSIONS: The presence of diabetes may negatively influence some aspects of IQ over time. Specific illness risk factors, such as an earlier age of disease onset and a history of hypoglycemic seizures, appear to put the young person at greater risk. Academic progress of children identified as at risk should be monitored and educational supports provided if necessary.

IGFBP-2 - taking the lead in growth, metabolism and cancer.

The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.

Turner syndrome patients with bicuspid aortic valves and renal malformations exhibit abnormal expression of X-linked inhibitor of apoptosis protein (XIAP).

OBJECTIVE: We analyzed mRNA expression of X-linked inhibitor of apoptosis protein (XIAP) in patients with Turner syndrome (TS) and examined its association with phenotypic features. SUBJECTS AND METHODS: XIAP mRNA expression levels were investigated in 98 patients with TS in total RNA extracted from blood leucocytes by real time quantitative polymerase chain reaction. RESULTS: Levels of XIAP mRNA were significantly lower in patients with bicuspid aortic valves (BAV; n=13) than those without (log XIAP -1.17±0.3 vs. -0.94±0.2, p=0.002). Significantly higher expression of XIAP mRNA was seen in patients with a mosaic karyotype and renal malformations (log XIAP -0.79±0.3 vs. -1.0±0.3, p=0.03). No correlations were seen between XIAP and other manifestations. CONCLUSION: Abnormal expression of XIAP may be an important underlying mechanism in the development of BAV and renal malformations in TS. However, abnormal XIAP mRNA expression, as determined from peripheral mononuclear cells, does not appear to explain all the somatic and visceral stigmata of TS.

C-5 propyne-modified oligonucleotides penetrate the epidermis in psoriatic and not normal human skin after topical application.

We have previously shown that antisense oligonucleotides effectively reduced insulin-like growth factor I receptor expression in human psoriatic skin grafted on to nude mice when injected intradermally. We therefore investigated the penetration of C-5 propyne modified antisense oligonucleotides into human normal and psoriatic skin after topical administration. Oligonucleotide (37.5 microg; 250 microM) was applied in aqueous solution or 5% methylcellulose gel for 24 h, prior to live confocal microscopy and fluorescence microscopy of fixed sections. We found that oligonucleotide could penetrate through the stratum corneum of psoriatic but not normal human skin over large regions of the epidermis. The oligonucleotide was localized to the nucleus of large parakeratotic cells in the psoriatic skin as well as smaller basal and suprabasal keratinocytes. In normal human skin, oligonucleotide was confined to the stratum corneum, with little or no oligonucleotide apparent in the viable epidermis. Electrophoresis of oligonucleotide recovered from treated psoriatic and normal skin revealed that the oligonucleotide remained intact over the 24 h period. In summary, we found that C-5 propyne modified antisense oligonucleotides could reach the target cells (in this case basal keratinocytes) after topical administration to psoriatic but not normal skin.