White matter, cognition and psychotic-like experiences in UK Biobank.

BACKGROUND: Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between white matter and PLEs. METHODS: We investigated two independent samples (6170 and 19 891) from the UK Biobank, through path analysis. For both samples, measures of whole-brain fractional anisotropy (gFA) and mean diffusivity (gMD), as indications of white matter microstructure, were derived from probabilistic tractography. For the smaller sample, variables whole-brain white matter network efficiency and microstructure were also derived from structural connectome data. RESULTS: The mediation of cognition on the relationships between white matter properties and PLEs was non-significant. However, lower gFA was associated with having PLEs in combination with distress in the full available sample (standardized ß = -0.053, p = 0.011). Additionally, lower gFA/higher gMD was associated with lower g-factor (standardized ß = 0.049, p < 0.001; standardized ß = -0.027, p = 0.003), and partially mediated by processing speed with a proportion mediated of 7% (p = < 0.001) for gFA and 11% (p < 0.001) for gMD. CONCLUSIONS: We show that lower global white matter microstructure is associated with having PLEs in combination with distress, which suggests a direction of future research that could help clarify how and why individuals progress from subclinical to clinical psychotic symptoms. Furthermore, we replicated that processing speed mediates the relationship between white matter microstructure and g-factor.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

Psychotic-like experiences, polygenic risk scores for schizophrenia, and structural properties of the salience, default mode, and central-executive networks in healthy participants from UK Biobank.

Schizophrenia is a highly heritable disorder with considerable phenotypic heterogeneity. Hallmark psychotic symptoms can be considered as existing on a continuum from non-clinical to clinical populations. Assessing genetic risk and psychotic-like experiences (PLEs) in non-clinical populations and their associated neurobiological underpinnings can offer valuable insights into symptom-associated brain mechanisms without the potential confounds of the effects of schizophrenia and its treatment. We leveraged a large population-based cohort (UKBiobank, N = 3875) including information on PLEs (obtained from the Mental Health Questionnaire (MHQ); UKBiobank Category: 144; N auditory hallucinations = 55, N visual hallucinations = 79, N persecutory delusions = 16, N delusions of reference = 13), polygenic risk scores for schizophrenia (PRSSZ) and multi-modal brain imaging in combination with network neuroscience. Morphometric (cortical thickness, volume) and water diffusion (fractional anisotropy) properties of the regions and pathways belonging to the salience, default-mode, and central-executive networks were computed. We hypothesized that these anatomical concomitants of functional dysconnectivity would be negatively associated with PRSSZ and PLEs. PRSSZ was significantly associated with a latent measure of cortical thickness across the salience network (r = -0.069, p = 0.010) and PLEs showed a number of significant associations, both negative and positive, with properties of the salience and default mode networks (involving the insular cortex, supramarginal gyrus, and pars orbitalis, pFDR < 0.050); with the cortical thickness of the insula largely mediating the relationship between PRSSZ and auditory hallucinations. Generally, these results are consistent with the hypothesis that higher genetic liability for schizophrenia is related to subtle disruptions in brain structure and may predispose to PLEs even among healthy participants. In addition, our study suggests that networks engaged during auditory hallucinations show structural associations with PLEs in the general population.

Os odontoideum in wolcott-rallison syndrome: a case series of 4 patients.

Wolcott-Rallison Syndrome is the commonest cause of neonatal diabetes in consanguineous families. It is associated with liver dysfunction, epiphyseal dysplasia, and developmental delay. It is caused by mutations in eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3).We report 4 children with WRS and Os Odontoideum resulting in significant neurological compromise. This cervical spine abnormality has not previously been described in this syndrome. This additional evidence broadens the clinical spectrum of this syndrome and confirms the role of EIF2AK3 in skeletal development. Furthermore, Os Odontoideum needs to be actively screened for in WRS patients to prevent neurological and respiratory compromise.

Temozolomide in the management of dopamine agonist-resistant prolactinomas.

BACKGROUND: The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment. CASE SERIES: We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16-year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT). LITERATURE REVIEW AND DISCUSSION: A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT-negative staining and a good response to temozolomide (OR 9.35, P = 0.0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.

Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome.

A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopathy and later skeletal epiphyseal dysplasia also became evident. His psychosocial development and educational achievements have remained within normal limits. While there were no clear biochemical indicators of a mitochondrial disorder, an almost complete deficiency of complex I of the respiratory chain was demonstrated in liver but not in fibroblast or muscle samples. Molecular analysis of the eukaryotic translation initiation factor 2alpha kinase gene (EIF2AK3) demonstrated a homozygous mutation, compatible with a diagnosis of Wolcott-Rallison syndrome (WRS). This patient's course adds a new perspective to the presentation of WRS caused by mutations in the EIF2AK3 gene linking it to mitochondrial disorders: recoverable and recurrent acute liver failure. The findings also illustrate the diagnostic difficulty of mitochondrial disease as it cannot be excluded by muscle or skin biopsy in patients presenting with liver disease. The case also further complicates the decision-making process for liver transplantation in cases of acute liver failure in the context of a possible mitochondrial disorder. Such patients may be more likely to recover spontaneously if a mitochondrial disorder underlies the liver failure, yet without neurological features liver transplantation remains an option.

Contextual detection of ischemic regions in ultra-wide-field-of-view retinal fluorescein angiograms.

We report a novel prototype algorithm using contextual knowledge to locate ischemic regions in ultra-wide-field-of-view retinal fluorescein angiograms. We use high-resolution images acquired by an Optos ultra-wide-field-of-view (more than 200 degrees) scanning laser ophthalmoscope. We leverage the simultaneous occurrence of ischemia with a number of other signs, detected automatically, typical for the state of progress of the condition in a diabetic patient. The specific nature of ischemic and non-ischemic regions is determined with an AdaBoost learning algorithm. Preliminary results demonstrate above 80% pixel classification accuracy against manual annotations.

Hepatic hemangioendothelioma associated with production of humoral thyrotropin-like factor.

We report on 7 patients referred for treatment of hepatic hemangioendothelioma with increased thyrotropin levels. The serum thyroxine level was decreased in 4 and increased in 2. Immunohistochemistry showed positive staining of tumor, but not of normal liver tissue, for thyrotropin. We propose secretion by the tumor of a thyrotropin-like factor.

The effect of short stature, portal hypertension, and cholestasis on growth hormone resistance in children with liver disease.

Chronic liver disease is associated with GH resistance, which is characterized by high circulating GH and low insulin-like growth factor I (IGF-I) concentrations. Standard GH replacement has no effect on serum IGF-I in pediatric liver disease. The aims were to examine whether GH resistance can be overcome by supraphysiological GH and to determine whether GH resistance worsens with the progression of liver disease. Thirty children, divided into five groups whose liver disease was at clinically different stages, were studied. They were given 0.2 IU/kg x day GH for 4 days and then 0.4 IU/kg x day for the next 4 days. Serum IGF-I and binding proteins (IGFBPs) were measured by immunoassay. IGF-I was lower in all study groups than in normal controls. IGF-I, IGFBP-3, and acid-labile subunit rose in response to GH. The magnitude of the response reflected nutritional status and liver dysfunction; in particular, portal hypertension was associated with a poor IGF-I response. There was no change in IGFBP-2. GH resistance begins early in the natural history of childhood liver disease and develops with the progression of liver disease, particularly with portal hypertension. It may be partially overcome by supraphysiological GH administration, but the effect becomes smaller with worsening liver disease.

New growth hormone receptor exon 9 mutation causes genetic short stature.

A novel form of congenital growth hormone insensitivity syndrome (GHIS), which lacks the classic phenotype associated with this condition, is described. Dominant inheritance is shown to result from a heterozygous 876-1 G to C transversion of the 3' splice acceptor site preceding exon 9 in the growth hormone receptor (GHR) gene. The result of this mutation is a severely truncated cytoplasmic domain of the GHR, which is incapable of transmitting a signal. The mutant receptor is shown to form a heterodimer with the wild-type GHR, the activity of which is inhibited in a dominant-negative manner.

Transport of surgically produced aerosols in an operating room.

The particle transport characteristics of two ventilation configurations commonly used in hospital operating rooms (ORs), cross-flow and impinging-flow ventilation, were investigated. The computational fluid dynamics software FLUENT was used to simulate turbulent airflow with mixed convection in a three-dimensional, rectangular OR. Two OR personnel, a patient, OR spotlights, an anesthetics cart, and an operating table were represented in the room. Heat loads from the personnel, patient, and lights affected the airflow through buoyancy. Particles produced at the operation site with various sizes and initial conditions were tracked through the room. A stochastic model was used to include the random effects of turbulence on particle trajectories. Simulation results show that heat loads from the personnel, patient, and OR spotlights had an important effect on the airflow through natural convection. Particle trajectories were influenced greatly by the flow field structure, particle launch position, and turbulence in the flow, and somewhat by particle size. However, particle paths were insensitive to the launch velocity. Virtually identical trajectories were obtained for particles with launch velocities ranging from 0 to 1 m/sec in magnitude. Changes in ventilation configuration dramatically affected particle transport. The cross-flow ventilation configuration performed better, based on the criteria of removing particles from the breathing zone of room occupants. Proper flow field design and contaminant source placement can be used to control particle transport. Numerical simulations allow quick and inexpensive comparisons between room designs and provide details about airflow and contaminant transport.

X-linked ichthyosis with hypogonadism: not always Kallmann's syndrome.

We describe two males with congenital ichthyosis secondary to steroid sulphatase deficiency who also manifested delayed puberty with biochemical features of hypogonadotrophic hypogonadism. In the first patient a history of cryptorchidism and the clinical findings of anosmia, micropenis and bimanual synkinesis suggested a contiguous gene syndrome, comprising X-linked Kallmann's syndrome and X-linked ichthyosis. An X-Y chromosomal translocation involving the Xp22.3 locus was identified; deletions of the STS locus and of exons 10-14 of the KAL locus were subsequently demonstrated. The second patient was euosmic and, although the STS locus was deleted in association with a pericentric inversion involving Xp22.3, no deletions were detected at the KAL locus. Clinically, he was felt to have constitutionally delayed puberty rather than hypogonadotropic hypogonadism and this diagnosis was substantiated by his subsequent development.

Orthotopic liver transplantation reverses the adverse nutritional changes of end-stage liver disease in children.

The changes in growth and body composition after orthotopic liver transplantation (OLT) were studied in 61 children [median age at OLT 3.49 y (range: 0.04-14.5 y), 26 boys and 35 girls] who had survived > or = 1 y post-OLT. Height, weight, midarm circumference (MAC), triceps skinfold thickness (TSF), and subscapular skinfold thickness (SSF) were measured at OLT, 3 and 6 mo later, then annually up to 5 y. SD scores (SDS) were derived from population standards. Results are reported as mean SDS +/- SEM. At OLT the children were short and malnourished (height: -0.98 +/- 0.22; weight -0.82 +/- 0.18; MAC: -1.77 +/- 0.21; TSF: -1.27 +/- 0.17; SSF: -1.49 +/- 0.17). By 3 mo post-OLT, there was a sustained improvement in MAC (-0.73 +/- 0.22), TSF (-0.48 +/- 0.18), and SSF (-0.50 +/- 0.18). Weight SDS (-0.48 +/- 0.20) improved by 6 mo without significant change in height SDS. The three children with Alagille syndrome were smaller (height, weight, and MAC) than children with other diagnoses but did show catch-up growth. Fulminant hepatic failure was not associated with growth failure before or after OLT. Infants (n = 14) were smaller and more malnourished at OLT (smaller skinfold thicknesses and lower weight SDS) than those who received transplants at an older age. By 1 y post-OLT, the only persisting difference was in TSF. Abnormal liver function at 1 y post-OLT (n = 8) and repeated episodes of steroid-treated rejection (n = 13) were associated with worsening height and weight SDS. The use of tacrolimus for graft salvage from rejection (n = 6) was not associated with growth failure. In conclusion, end-stage liver disease has a more adverse effect on MAC, TSF, and SSF than on height and weight, but a marked and rapid improvement occurred post-OLT. Children who were most severely malnourished and growth restricted at the time of OLT showed the greatest catch-up growth after OLT.

Identification, localization, and regulation of insulin-like growth factor binding proteins and their messenger ribonucleic acids in the newborn rat olfactory bulb.

Insulin-like growth factor binding proteins (IGFBPs) have been identified in most tissues, including the central nervous system, where the major IGFBPs have been localized. The regulation and roles of IGFBPs in IGF action in the developing brain remain unclear. In this study we examined the expression and anatomical distribution of IGFBP messenger RNAs (mRNAs) in the newborn rat olfactory bulb (OB) during the first postnatal week. We used our recently developed newborn rat OB organ culture system, which emulates the first week of in vivo development, to identify and characterize expressed and secreted IGFBPs and to determine the role of the local growth factors IGF-I and basic fibroblast growth factor (bFGF) in their regulation. Postnatal day 1 rat OBs were cultured serum free for 6 days in the absence or presence of IGF-I (150 ng/ml) and bFGF (25 ng/ml), alone or in combination, as previously shown by us to maintain morphology and differentiation of neuronal and glial cells. Conditioned medium was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western ligand blotting using [125I]IGF-I, and IGFBPs were characterized by immunoprecipitation. Western ligand blotting of conditioned medium revealed two bands at 24 kilodaltons (kDa) and 30 kDa and a doublet at 38-42 kDa. All bands were enhanced by IGF-I treatment, whereas bFGF enhanced the 24-kDa and 30-kDa bands only. In combination, IGF-I and bFGF enhanced all four bands above that seen with either growth factor alone. Total RNA was extracted from fresh day 1, day 6, and cultured OBs for Northern blotting using complementary DNA probes for IGFBP-2, -3, -4, and -5. In fresh day 1 OBs, mRNA was detected for IGFBP-2, -4, and -5, but not for IGFBP-3. In fresh day 6 OBs IGFBP-2 mRNA was more abundant, whereas IGFBP-4 mRNA showed lower expression than at day 1, and IGFBP-5 mRNA was similarly expressed. When day 1 OBs were cultured for 6 days, mRNA was also readily detected for IGFBP-2, -4, and -5, but not for IGFBP-3. All detected mRNA species were enhanced by IGF-I. Basic FGF enhanced IGFBP-2 mRNA whether alone or in combination with IGF-I and enhanced only IGFBP-4 mRNA when given alone. IGFBP-5 mRNA was not affected by bFGF alone, but its enhancement by IGF-I was attenuated by bFGF. Sites of transcription of IGFBP and IGF-I mRNAs were located by in situ hybridization in both fresh and cultured bulbs.(ABSTRACT TRUNCATED AT 400 WORDS)

The evolution of changes in immunoreactive serum insulin-like growth factors (IGFs), IGF-binding proteins, circulating growth hormone (GH) and GH-binding protein as a result of short-term dexamethasone treatment.

Inhibition of growth in man and laboratory animals by glucocorticoid treatment is well recognized, yet we have previously shown that glucocorticoids may paradoxically enhance GH secretion and increase serum insulin-like growth factor (IGF) levels. IGFs circulate bound to high-affinity binding proteins (IGFBPs) which modulate their actions, and circulating GH may be associated with two binding proteins (GHBPs) of which the high-affinity GHBP has been characterized and is structurally identical to the extracellular domain of the GH receptor. We have investigated the time-course of changes in GH, IGFs and their binding proteins induced by glucocorticoid treatment in normal male volunteers (n = 12, age range 22-31 years) sampled at 0800 h daily before and during treatment with dexamethasone (2 mg twice daily) for 5 days. In addition, subjects were sampled at 30-min intervals over 7-h periods (0730-1430 h) during the day prior to dexamethasone (day 0), on day 1 following the first dose of dexamethasone and on day 5 following the last dose of dexamethasone. Mean serum IGF-I rose over the initial 72 h and remained elevated at 96 h (297 +/- 11.5 compared with basal levels of 215.5 +/- 9.3 micrograms/l, P < 0.001) whereas IGF-II levels did not change (472.6 +/- 20.5 vs 450.3 +/- 21.7 micrograms/l, P = 0.97). There was a concomitant rise in serum IGFBP-3 from basal levels of 3.69 +/- 0.23 mg/l to a peak at 5 days of 4.16 +/- 0.21 (P = 0.003 vs day 1).(ABSTRACT TRUNCATED AT 250 WORDS)

A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization.

Growth hormone (GH) elicits a variety of biological activities mainly mediated by the GH receptor (GHR), a transmembrane protein that, based on in vitro studies, seemed to function as a homodimer. To test this hypothesis directly, we investigated patients displaying the classic features of Laron syndrome (familial GH resistance characterized by severe dwarfism and metabolic dysfunction), except for the presence of normal binding activity of the plasma GH-binding protein, a molecule that derives from the exoplasmic-coding domain of the GHR gene. In two unrelated families, the same GHR mutation was identified, resulting in the substitution of a highly conserved aspartate residue by histidine at position 152 (D152H) of the exoplasmic domain, within the postulated interface sequence involved in homodimerization. The recombinant mutated receptor protein was correctly expressed at the plasma membrane. It displayed subnormal GH-binding activity, a finding in agreement with the X-ray crystal structure data inferring this aspartate residue outside the GH-binding domain. However, mAb-based studies suggested the critical role of aspartate 152 in the proper folding of the interface area. We show that a recombinant soluble form of the mutant receptor is unable to dimerize, the D152H substitution also preventing the formation of heterodimers of wild-type and mutant molecules. These results provide in vivo evidence that monomeric receptors are inactive and that receptor dimerization is involved in the primary signalling of the GH-associated growth-promoting and metabolic actions.

Smoking health risk. Counseling of psychiatric patients.

1. Cigarette smoking has been identified as the single most important source of preventable morbidity and premature mortality in the United States for each of the past 25 years. Despite a smoking rate of 50% to 84%, persons with psychiatric illness have not been the target of any documented smoking health risk education in current literature. 2. Most nurses view smoking health risk education as a nursing function, but few actually provide this care for patients due to perceived ineffectiveness of health risk education, belief that smoking is not a health risk, and lack of knowledge base to provide the care. 3. Data from the study reported on in the article reflected that nurses were providing smoking health risk information to less than 50% of patients. Nurses were not identifying nicotine dependence as a nursing problem and therefore were making no plans to provide nursing interventions to resolve it.

Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery.

OBJECTIVE: The aim was to study the pharmacokinetic parameters and biological activity of a single dose of human recombinant IGF-I (rhIGF-I) administered to patients following major gastrointestinal surgery. DESIGN: A double blind placebo controlled externally randomized study of 30 patients; the study commencing 24 hours after major colonic or gastric surgery. MEASUREMENTS: After a baseline blood sampling day, IGF-I (40 micrograms/kg by single subcutaneous dose, n = 20) or placebo (n = 10) was administered and serum and urine samples collected over the ensuing 72 hours. Serum IGF-I, IGF-II, IGF binding proteins (IGFBP-1, IGFBP-3), GH and insulin were measured by radioimmunoassay. Serum IGF bioactivity was assessed using a validated porcine cartilage bioassay. Serum and urinary electrolytes were measured by standard methodology. RESULTS: Serum immunoreactive IGF-I levels peaked at 4 hours following injection of IGF-I (1.09 +/- 0.12 U/ml mean +/- SEM), remained elevated for 15 hours and returned to basal levels by 24 hours after injection. IGF bioactivity was increased by 57% 6 hours after IGF-I injection. Mean levels of IGFBP-1 and IGFBP-3, IGF-II and GH were unaffected by IGF-I administration. Insulin levels were suppressed at 30 minutes following injection of IGF-I compared with the placebo group (16.9 +/- 3.0 mU/I vs 32.3 +/- 7.1, P = 0.02); thereafter, there were no differences in insulin levels. The mean change in serum creatinine following IGF-I (-6.3 +/- 3.0 mmol/l) was significantly different from that in the control group (+7.2 +/- 6.2, P = 0.03). Creatinine clearance rose from a mean of 71.6 +/- 7.5 ml/min to 83.2 +/- 7.6 ml/min after IGF-I treatment (P = 0.02). In the IGF treated patients, cholesterol levels consistently fell (-0.20 +/- 0.05 mmol/l); this was not observed in the placebo group (+0.20 +/- 0.14, P = 0.006). Basal serum potassium levels in the IGF treatment group (4.1 +/- 0.1 mmol/l) fell to 3.8 +/- 0.1 at 4 hours (P = 0.002) and 3.6 +/- 0.1 at 10 hours (P = 0.001) returning to a level of 4.0 +/- 0.1 (P = 0.293) at 24 hours after injection. There were no other observed differences in serum or urinary electrolytes or serum free fatty acids and triglycerides. Pharmacokinetic parameters derived from baseline adjusted IGF-I measurements revealed a slow absorption of the administered dose with a Tmax of 5.0 +/- 0.43 hours and an elimination half-life of 10.8 +/- 1.2 hours. The computed volume of distribution was 0.33 +/- 0.05 I/kg and the clearance on average 25 ml/min. CONCLUSION: A single subcutaneous dose of IGF-I normalized circulating IGF-I levels in post-operative patients, was well tolerated and without side-effects. IGF bioactivity was increased and associated with a fall in serum cholesterol, potassium and creatinine levels and a rise in creatinine clearance. Further long-term studies are now required to assess the anabolic effects of rhIGF-I in this type of patient group.