Intrathecal drug delivery in the era of nanomedicine.

Administration of substances directly into the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord is one approach that can circumvent the blood-brain barrier to enable drug delivery to the central nervous system (CNS). However, molecules that have been administered by intrathecal injection, which includes intraventricular, intracisternal, or lumbar locations, encounter new barriers within the subarachnoid space. These barriers include relatively high rates of turnover as CSF clears and potentially inadequate delivery to tissue or cellular targets. Nanomedicine could offer a solution. In contrast to the fate of freely administered drugs, nanomedicine systems can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents within the CNS. Some evidence suggests that certain nanomedicine agents can reach the parenchyma following intrathecal administration. Here, we will address the preclinical and clinical use of intrathecal nanomedicine, including nanoparticles, microparticles, dendrimers, micelles, liposomes, polyplexes, and other colloidalal materials that function to alter the distribution of molecules in tissue. Our review forms a foundational understanding of drug delivery to the CSF that can be built upon to better engineer nanomedicine for intrathecal treatment of disease.

Fate of nanoparticles in the central nervous system after intrathecal injection in healthy mice.

Cerebrospinal fluid (CSF) is produced in the cerebral ventricles and circulates within the subarachnoid space (SAS) of the brain and spinal cord, where it exchanges with interstitial fluid of the parenchyma. The access of CSF to the entire central nervous system (CNS) makes it an attractive medium for drug delivery. However, few intrathecal (IT) therapies have reached the clinic due, in part, to limited distribution and rapid clearance. Given the success of nanoparticle (NP) carriers in prolonging circulation and improving delivery of systemically administered agents, we sought to evaluate the distribution of IT injected NPs within the CNS. We administered fluorescent, 100 nm PEGylated-NPs into the cisterna magna of healthy mice and studied their distribution along the brain and spinal cord. Our data demonstrate that NPs are capable of distributing rapidly through the SAS along the entire neuraxis with reproducible, anatomically defined patterns of delivery. NPs were well retained within the leptomeninges for over 3 weeks, showing preference for ventral surfaces and minimal penetration into the CNS parenchyma. Clearance of NPs occurred across the cribriform plate into the nasal mucosa, with a small fraction of NPs localizing with nerve roots exiting the spinal column. Larger 10 µm particles were also capable of moving through the SAS but did not achieve as widespread distribution. These studies demonstrate the ability of NPs to achieve widespread delivery along the neuraxis and highlight IT administration as a potentially significant route of administration for delivery of nanomedicine to the subarachnoid space.

Coming Up Short: Risks of Bias in Assessing Psychological Outcomes in Growth Hormone Therapy for Short Stature.

CONTEXT: Two often cited assumptions for treating children with GH are that short stature (SS), as an isolated physical characteristic, is associated with psychosocial morbidity and that GH treatment may increase height and improve psychological adjustment. Findings across studies regarding the psychological consequences associated with GH management of children with SS are variable and frequently contradictory. The purpose of this systematic review is to evaluate the degree to which any conclusions about the relative risks or benefits of GH treatment on psychological outcomes can be made based on the published literature. EVIDENCE ACQUISITION: Electronic databases were searched for randomized clinical trials and nonrandomized studies, published between 1958-2014, in which GH was administered for management of children with SS and psychosocial, cognitive, academic, or health-related quality of life outcomes were assessed. Methodological quality of each study was assessed using the Cochrane Collaboration's tool for assessing risk of bias. EVIDENCE SYNTHESIS: Eighty studies were evaluated. No studies were rated as having a low risk of bias, the risk of bias was unclear in seven study outcome areas, and the remaining studies were judged as having a high risk of bias. CONCLUSIONS: The high risk of bias present in the majority of the literature on GH treatment effects on psychological outcomes (in particular, lack of blinding) substantially weakens confidence in their results. This may serve to explain the variability of findings for these outcomes across studies.

Disorders of Sex Development (DSD): Networking and Standardization Considerations.

Syndromes resulting in Disorders of Sex Development (DSD) are individually rare. Historically, this fact has hindered both clinical research and the delivery of evidence-based care. Recognizing the need for advancement, members of European and North American medical societies produced policy statements, notably the Consensus Statement on Management of Intersex Disorders, which recognize that optimal healthcare in DSD requires multidisciplinary teams in conjunction with networking of treatment centers and continued development of patient registries. This paper summarizes efforts in Europe and the U.S. toward creating networks focused on expanding discovery and improving healthcare and quality of life outcomes in DSD. The objectives and function of registry-based networks (EuroDSD/I-DSD), learning collaboratives (DSD-net), clinical outcomes research (DSD-Life), and networking hybrids (DSD-TRN) are reviewed. Opportunities for, and barriers to standardization in research and care are highlighted in light of practical considerations, for example, limitations in reliably classifying anatomic phenotypes and gaps in behavioral health staffing resources. The role of patient-reported outcomes is considered, with emphasis on integrating patient perspectives, given findings of limited agreement in outcome ratings by healthcare providers and patients. Finally, the characteristics of clinical centers likely to deliver the highest quality outcomes are discussed.

Promoting Shared Decision Making in Disorders of Sex Development (DSD): Decision Aids and Support Tools.

Specific complaints and grievances from adult patients with disorders of sex development (DSD), and their advocates center around the lack of information or misinformation they were given about their condition and feeling stigmatized and shamed by the secrecy surrounding their condition and its management. Many also attribute poor sexual function to damaging genital surgery and/or repeated, insensitive genital examinations. These reports suggest the need to reconsider the decision-making process for the treatment of children born with DSD. This paper proposes that shared decision making, an important concept in adult health care, be operationalized for the major decisions commonly encountered in DSD care and facilitated through the utilization of decision aids and support tools. This approach may help patients and their families make informed decisions that are better aligned with their personal values and goals. It may also lead to greater confidence in decision making with greater satisfaction and less regret. A brief review of the past and current approach to DSD decision making is provided, along with a review of shared decision making and decision aids and support tools. A case study explores the need and potential utility of this suggested new approach.

Parenting Children with Disorders of Sex Development (DSD): A Developmental Perspective Beyond Gender.

Advances in therapeutics for specific conditions have contributed to a categorical psychological approach to chronic diseases that affect children. Consensus statements and clinical guidelines recognize stress associated with disorders of sex development (DSD) for patients and their caregivers - yet much remains to be learned concerning the social adjustment, mental health, and quality of life of affected children and their families. We present preliminary data on the psychosocial comorbidities of caregivers of children with DSD, including stigma, isolation, stress, anxiety, and depressive symptomatology. Evidence is offered in support of individualized psychological approaches for families according to such variables as: 1) gender of the caregiver, 2) gender of the affected child and 3) presence of genital ambiguity at birth. Development of feasible, targeted interventions to ameliorate psychosocial comorbidities among caregivers is needed to optimize social adjustment, mental health, and health-related quality of life (HRQoL) for children with DSD.

Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies.

Charged meson rapidity distributions in central Au+Au collisions at square root(sNN) = 200 GeV.

We have measured rapidity densities dN/dy of pi+/- and K+/- over a broad rapidity range (-0.1 < y < 3.5) for central Au + Au collisions at square root(sNN) = 200 GeV. These data have significant implications for the chemistry and dynamics of the dense system that is initially created in the collisions. The full phase-space yields are 1660 +/- 15 +/- 133 (pi+), 1683 +/- 16 +/- 135 (pi-), 286 +/- 5 +/- 23 (K+), and 242 +/- 4 +/- 19 (K-). The systematics of the strange to nonstrange meson ratios are found to track the variation of the baryochemical potential with rapidity and energy. Landau-Carruthers hydrodynamics is found to describe the bulk transport of the pions in the longitudinal direction.

Centrality dependence of charged-particle pseudorapidity distributions from d + Au collisions at sqrt[sNN] = 200 GeV.

Charged-particle pseudorapidity densities are presented for the d + Au reaction at sqrt[s(NN)] = 200 GeV with -4.2 < or = eta < or = 4.2. The results, from the BRAHMS experiment at BNL Relativistic Heavy-Ion Collider, are shown for minimum-bias events and 0%-30%, 30%-60%, and 60%-80% centrality classes. Models incorporating both soft physics and hard, perturbative QCD-based scattering physics agree well with the experimental results. The data do not support predictions based on strong-coupling, semiclassical QCD. In the deuteron-fragmentation region the central 200 GeV data show behavior similar to full-overlap d+Au results at sqrt[s(NN)] = 19.4 GeV.

Nuclear stopping in Au+Au collisions at square root of S(NN)=200 GeV.

Transverse momentum spectra and rapidity densities, dN/dy, of protons, antiprotons, and net protons (p-p) from central (0%-5%) Au+Au collisions at square root of S(NN)=200 GeV were measured with the BRAHMS experiment within the rapidity range 0

Evolution of the nuclear modification factors with rapidity and centrality in d + Au collisions at (sqrt)[N(S)N]=200 GeV.

We report on a study of the transverse momentum dependence of nuclear modification factors R(dAu) for charged hadrons produced in deuteron + gold collisions at sqrt[s(NN)]=200 GeV, as a function of collision centrality and of the pseudorapidity (eta=0, 1, 2.2, 3.2) of the produced hadrons. We find a significant and systematic decrease of R(dAu) with increasing rapidity. The midrapidity enhancement and the forward rapidity suppression are more pronounced in central collisions relative to peripheral collisions. These results are relevant to the study of the possible onset of gluon saturation at energies reached at BNL RHIC.

Transverse-momentum spectra in Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV and the pseudorapidity dependence of high-p(T) suppression.

We present spectra of charged hadrons from Au+Au and d+Au collisions at sqrt[s(NN)]=200 GeV measured with the BRAHMS experiment at RHIC. The spectra for different collision centralities are compared to spectra from p+(-)p collisions at the same energy scaled by the number of binary collisions. The resulting ratios (nuclear modification factors) for central Au+Au collisions at eta=0 and eta=2.2 evidence a strong suppression in the high p(T) region (>2 GeV/c). In contrast, the d+Au nuclear modification factor (at eta=0) exhibits an enhancement of the high p(T) yields. These measurements indicate a high energy loss of the high p(T) particles in the medium created in the central Au+Au collisions. The lack of suppression in d+Au collisions makes it unlikely that initial state effects can explain the suppression in the central Au+Au collisions.

Rapidity dependence of charged antihadron to hadron ratios in Au+Au collisions at sqrt[s(NN)]=200 GeV.

We present ratios of the numbers of charged antihadrons to hadrons (pions, kaons, and protons) in Au+Au collisions at sqrt[s(NN)]=200 GeV as a function of rapidity in the range y=0-3. While the ratios at midrapidity are approaching unity, the K(-)/K(+) and p;/p ratios decrease significantly at forward rapidities. An interpretation of the results within the statistical model indicates a reduction of the baryon chemical potential from mu(B) approximately 130 MeV at y=3 to mu(B) approximately 25 MeV at y=0.

Pseudorapidity distributions of charged particles from Au + Au collisions at the maximum RHIC energy, square root[s(NN)] = 200 GeV.

We present charged-particle multiplicities as a function of pseudorapidity and collision centrality for the 197Au+197Au reaction at square root[s(NN)] = 200 GeV. For the 5% most central events we obtain dN(ch)/deta/(eta = 0) = 625+/-55 and N(ch)/(-4.7< or =eta < or =4.7) = 4630 +/- 370, i.e., 14% and 21% increases, respectively, relative to square root[s(NN)] = 130 GeV collisions. Charged-particle production per pair of participant nucleons is found to increase from peripheral to central collisions around midrapidity. These results constrain current models of particle production at the highest RHIC energy.

Psychosocial adaptation of middle childhood boys with hypospadias after genital surgery.

OBJECTIVE: To compare the psychosocial adaptation of boys with hypospadias after genital surgery to a community sample. METHODS: Boys (6 to 10 years) with a history of hypospadias repair (n = 175) were compared with a community sample (n = 333) in a postal questionnaire survey using the Child Behavior Checklist. RESULTS: Few significant differences between cases and controls emerged. Boys with hypospadias were (slightly) lower in social involvement but did not perform more poorly in school. Boys with hypospadias displayed fewer externalizing behavior problems than controls, but a significant difference in nocturnal enuresis was not detected. Level of behavior problems did not differentiate hypospadias severity subgroups, but greater surgical and hospitalization experiences were associated with increased internalizing problems. Poorer cosmetic appearance of the genitals was associated with worse school performance. CONCLUSIONS: Surgically corrected hypospadias should not be considered a risk factor for poor psychosocial adaptation in childhood, but emotional problems increase with the number of hospital-related experiences.

Information processing of an acquaintance rape scenario among high- and low-dissociating college women.

To assess the impact of dissociation on information processing, 66 college women with high and low levels of trait dissociation were studied with regard to how they unitized videotape segments of an acquaintance rape scenario (actual assault not shown) and a nonthreatening control scenario. Unitization is a paradigm that measures how actively people process stimuli by recording how many times they press a button to indicate that they have seen a significant or meaningful event. Trait dissociation was negatively correlated with participants' unitization of the acquaintance rape videotape, unitization was positively correlated with danger cue identification, and state dissociation was negatively correlated with dangerousness ratings.

Spontaneous intraparenchymal hemorrhage in full-term neonates.

OBJECTIVE: Spontaneous intraparenchymal hemorrhage is extremely rare in full-term newborns. Reports to date have been limited to descriptions of individual cases, small groups within larger studies of intracranial hemorrhage, and one series of four patients. Structural lesions are rarely identified, and the majority of patients described have been managed without surgical intervention. METHODS: Analysis of a computerized database of pediatric neurosurgical patients from January 1960 to February 2000 identified full-term newborns younger than 3 months of age with nontraumatic intraparenchymal hemorrhages. Prenatal histories, labor and delivery histories, clinical presentations, imaging studies, management, and outcomes were reviewed. RESULTS: Eleven full-term newborns with spontaneous intraparenchymal hemorrhages were identified. The majority had normal prenatal courses. Most presented within the first 2 days of life (6 of 11 patients), and the most common presenting sign was seizure (7 of 11 patients). No cause was identified in 6 of 11 patients; the remainder were attributed to coagulopathy (n = 3), ruptured intracranial aneurysm (n = 1), or hemorrhagic infarction (n = 1). Eight patients underwent surgical hematoma evacuation on the basis of radiographic evidence of significant mass effect, evidence of signs of elevated intracranial pressure, or both. Three patients did not receive surgical intervention. There were no subsequent hemorrhages or deaths during a mean follow-up period of 4.5 years (range, 1-16 yr). Four patients had normal neurological outcomes, four had motor deficits (one of whom additionally demonstrated cognitive delay), and three had delayed speech. CONCLUSION: No cause is identified in most newborns with spontaneous intraparenchymal hemorrhage. Radiographic evidence of mass effect or signs of elevated intracranial pressure may necessitate surgical hematoma evacuation. Outcome varies widely and may be normal, even in patients with sizeable intraparenchymal hemorrhages.

MIB-1 staining index of pediatric meningiomas.

OBJECTIVE: For adult meningiomas, the staining index (SI) for the anti-Ki-67 monoclonal antibody MIB-1 is well correlated with histological atypia and tumor recurrence. MIB-1 SIs for meningiomas in the pediatric population have not been previously reported. Meningiomas tend to be more histologically aggressive and to recur more frequently in children, compared with adults. The objectives of this study were to determine whether MIB-1 SIs are correlated with pathological atypia and recurrence among pediatric meningiomas and to compare the MIB-1 SIs of pediatric meningiomas with those of adult meningiomas. METHODS: MIB-1 SIs were assessed on paraffin-embedded sections of 14 pediatric meningiomas (patient age, 2-17 yr), 5 of which contained atypical or malignant features. For comparison with benign pediatric meningiomas, MIB-1 SIs were also assessed on paraffin-embedded sections of 14 adult meningiomas (patient age, 38-90 yr), none of which displayed atypical or malignant features or recurred within a 5-month median follow-up period. RESULTS: MIB-1 SIs of pediatric meningiomas ranged from 1.2 to 31.6% (median, 9.1%). Significant differences were observed between the MIB-1 SIs for tumors with atypical or malignant features (median, 12.3%; range, 7.0-31.6%) and those for tumors without atypia (median, 7.0%; range, 1.2-12.6%; P = 0.045). There were six recurrences after gross total resection, during a 36.5-month median follow-up period. All five of the tumors with pathological atypia recurred; one tumor without atypia recurred. Significant differences were observed between MIB-1 SIs for nonrecurrent tumors (median, 6.6%; range, 1.2-12.2%) and those for recurrent tumors (median, 12.5%; range, 7.0-31.6%; P = 0.012). The median MIB-1 SI for adult control specimens was 8.8% (range, 1.2-19.3%), which did not differ significantly from that for pediatric meningiomas without atypia (P = 0.68). CONCLUSION: For this cohort of pediatric meningiomas, pathological atypia and the tendency to recur were correlated with elevated MIB-1 SIs. The median MIB-1 SI for pediatric meningiomas without histological atypia did not differ significantly from that for adult meningiomas without atypia, suggesting that the more aggressive clinical features of meningiomas in children may be attributable to factors other than the rate of cellular proliferation.

Endoscopic biopsy for tumors of the third ventricle.

Twelve patients underwent endoscopic biopsy of a tumor involving the third ventricle. Nine patients had no significant medical history while 3 had a history of cancer. Unique characteristics of each case dictated the optimal surgical technique. Endoscopic tumor biopsy was combined with additional procedures in 9 cases; shunt insertion (3), shunt insertion with endoscopic septostomy (5), and transcallosal craniotomy (1). Diagnosis was established in 11 patients (92%); 6 primary brain tumors, 3 metastatic central nervous system tumors, 1 metastatic systemic cancer, and 1 region of post-treatment gliosis. One case was aborted due to poor visualization. Therapy was directly influenced by endoscopic biopsy in 11/12 cases (92%) and craniotomy for tumor resection was avoided in 10/12 patients (83%). Of the 5 patients who underwent endoscopic septostomy, 4 required no subsequent procedures for hydrocephalus. There were no complications, and hospital stay averaged 1.78 days for patients who underwent successful endoscopic biopsy. Tumors of the third ventricle are amenable to endoscopic biopsy with excellent diagnostic yield and low morbidity. The procedure must be tailored depending upon the tumor location within the third ventricle, the degree of ventriculomegaly, and the need to perform a septostomy. Singularly or combined with other endoscopic procedures, patients can be spared multiple and more invasive surgical procedures.

Perceived versus measured height. Which is the stronger predictor of psychosocial functioning?

The relationship between perceptions versus measured height and children's psychosocial adaptation in a sample of medically referred youth with short stature was investigated. All children referred for a growth evaluation to one regional pediatric endocrinology clinic received a psychosocial screening assessment as a routine component of their initial visit. Data were collected for patients ages 4-18 years (n = 620) with heights ranging from -4.0 to -1.1 SD for age- and gender-adjusted population norms. Patients (8 years and older) and in all cases a parent/guardian served as informant through paper-and-pencil questionnaires. Both children and parents overestimated the child's height. Overestimations of height were associated with greater patient and parent satisfaction with stature. Perceived height was more strongly associated with psychosocial adaptation than was measured height. Clinical management decisions designed to enhance patient quality of life by increasing projected adult height through hormonal interventions should take into account both measured and perceived patient height.