Characterization of MR Imaging-Visible Perivascular Spaces in the White Matter of Healthy Adolescents at 3T.

BACKGROUND AND PURPOSE: Perivascular spaces play a role in cerebral waste removal and neuroinflammation. Our aim was to provide data regarding the burden of MR imaging-visible perivascular spaces in white matter in healthy adolescents using an automated segmentation method and to establish relationships between common demographic characteristics and perivascular space burden. MATERIALS AND METHODS: One hundred eighteen 12- to 21-year-old subjects underwent T1- and T2-weighted 3T MR imaging as part of the National Consortium on Alcohol and Neurodevelopment in Adolescence. Perivascular spaces were identified in WM on T2-weighted imaging using a local heterogeneity approach coupled with morphologic constraints, and their spatial distribution and geometric characteristics were assessed. RESULTS: MR imaging-visible perivascular spaces were identified in all subjects (range, 16-287). Males had a significantly higher number of perivascular spaces than females: males, mean, 98.4 ± 50.5, versus females, 70.7 ± 36.1, (P < .01). Perivascular space burden was bilaterally symmetric (r > 0.4, P < .01), and perivascular spaces were more common in the frontal and parietal lobes than in the temporal and occipital lobes (P < .01). Age and pubertal status were not significantly associated with perivascular space burden. CONCLUSIONS: Despite a wide range of burden, perivascular spaces are present in all healthy adolescents. Perivascular space burden is higher in adolescent males than in females, regardless of age and pubertal status. In this population, perivascular spaces are highly symmetric. Although widely reported as a feature of the aging brain, awareness of the presence of perivascular spaces in a cohort of healthy adolescents provides the foundation for further research regarding the role of these structural variants in health and disease.

Striatal dopamine D1-type receptor availability: no difference from control but association with cortical thickness in methamphetamine users.

Chronic methamphetamine use poses potentially devastating consequences for directly affected individuals and for society. Lower dopamine D2-type receptor availability has been observed in striata of methamphetamine users as compared with controls, but an analogous comparison of D1-type receptors has been conducted only on post-mortem material, with no differences in methamphetamine users from controls in the caudate nucleus and putamen and higher D1-receptor density in the nucleus accumbens. Released from neurons when methamphetamine is self-administered, dopamine binds to both D1- and D2-type receptors in the striatum, with downstream effects on cortical activity. Thus, both receptor subtypes may contribute to methamphetamine-induced alterations in cortical morphology and behavior. In this study, 21 methamphetamine-dependent subjects and 23 healthy controls participated in positron emission tomography and structural magnetic resonance imaging for assessment of striatal D1- and D2-type receptor availability and cortical gray-matter thickness, respectively. Although D2-type receptor availability (BPnd) was lower in the methamphetamine group, as shown previously, the groups did not differ in D1-type BPnd. In the methamphetamine group, mean cortical gray-matter thickness was negatively associated with cumulative methamphetamine use and craving for the drug. Striatal D1-type but not D2-type BPnd was negatively associated with global mean cortical gray-matter thickness in the methamphetamine group, but no association was found between gray-matter thickness and BPnd for either dopamine receptor subtype in the control group. These results suggest a role of striatal D1-type receptors in cortical adaptation to chronic methamphetamine use.

Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: link to impulsivity in methamphetamine users.

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.

Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users.

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

Effect of low-dose cyclosporine A in the treatment of refractory proteinuria in childhood-onset lupus nephritis.

We performed a prospective study to evaluate the efficacy and safety of low-dose cyclosporine A (CSA) treatment in paediatric lupus nephritis refractory to conventional therapy. Seven children with biopsy-proven Class III-IV lupus nephritis were treated with CSA (2-4 mg/kg/day) combined with low-dose prednisone for one year. All patients had failed to achieve sustained proteinuria remission with corticosteroids and cytotoxic drugs. Proteinuria decreased from median value of 2.5 g/24 hours (range, 1.2-4.9) to 0.14 g/24 hours (range, 0.0-0.84) after treatment (P = 0.018). Median values of creatinine clearance and serum creatinine did not change significantly. Median systemic lupus erythematosus disease activity index score decreased from 12 (range, 6-16) to 4 (range, 0-8) at end of treatment (P = 0.027). However, two patients experienced flares of extrarrenal manifestations and complement levels did not improve. Moreover, most patients relapsed with proteinuria within a few months of stopping CSA therapy. Side effects were not significant. In conclusion, low-dose of CSA combined with steroids appears to be useful to reduce proteinuria in paediatric proliferative lupus nephritis refractory to steroids and cytotoxic drugs; however, relapses are common after CSA discontinuation. Further studies are needed to define the precise role of CSA in paediatric lupus nephritis.

The mechanics of corporal veno-occlusion in penile erection: a theory on the effect of stretch-associated luminal constrictability on outflow resistance.

In order to further our understanding of the physiology of corporal veno-occlusion, we developed a theory of a possible contribution to corporal venous outflow resistance which occurs as the result of venule stretching with resultant luminal narrowing when penile volume increases during the erection process. We stretched non-biological tubes and rabbit abdominal vena cava segments, performed flow-based and volume-based experiments to calculate the magnitude of N, the newly defined 'stretch-associated luminal constrictability' factor. We solved for (R(s)/R(u)), the ratio of the venule fluid resistance in the stretched state (R(s)) to the unstretched state (R(u)), to quantify the projected increases in fluid resistance as well as Q.R(u) where Q is the subtunical venule flow rate. For a given tube, N was found to be essentially constant for different amounts of stretch. A theory was formulated which predicted R(s) and Q as a function of N, DeltaP (intracavernosal pressure increase); V(E)/V(F) (tunical distensibility); X (cavernosal expandability) and R(u). Based on the magnitude of N=2, this theory predicts that patients with the highest values of both V(E)/V(F) and X would have maximal R(s) values, approaching infinity (complete occlusion) at a low DeltaP near 5 mmHg. In contrast, patients with low values of both V(E)/V(F) (eg Peyronie's disease) and X (eg corporal fibrosis), would be predicted to have minimal R(s) values. For example, a hypothetical patient with the lowest values of V(E)/V(F) and X would yield R(s) values only approaching 7.9 times that of unstretched values at a DeltaP increase of 90 mmHg. We concluded to that stretch-associated venule resistance may occur as a result of decreased sub-tunical venule diameter and increased sub-tunical venule length. In individual patients, stretch-associated venule resistance may either dominate or be a minor component of the overall mechanism of corporal veno-occlusion.

Pharmacokinetics, biodistribution and dosimetry of 99mTc-labeled anti-human epidermal growth factor receptor humanized monoclonal antibody R3 in rats.

The pharmacokinetics, biodistribution and dosimetry of 99mTc-labeled anti-human epidermal growth factor receptor (anti-hEGF-r) humanized monoclonal antibody (MAb) R3 was investigated following intravenous injection in normal Wistar rats. Serum disappearance curves were best fit by a two-compartment model having a mean distribution half-life (t 1/2alpha) of 0.250 h and a mean elimination (t 1/2beta) of 13.89 h. Among the various organs, a little accumulation of the radiolabeled antibody was found only in kidneys. Biodistribution and dosimetry studies in humans were performed by extrapolation of the animal data to humans. Absorbed dose to normal organs and the remainder of the whole body were estimated using the medical internal radiation dose formula, and dose contributions from radioactivity in transit through the gastrointestinal tract were estimated using a compartment model. Extrapolated values of radiation absorbed dose to normal organs in rads per millicurie administered were whole body, 0.0085; lower large intestine wall, 0.0898; small intestine, 0.0530; upper large intestine wall, 0.0731; and kidneys, 0.0455. The effective dose equivalent predicted was 0.0162 rem/mCi and the effective dose was found to be 0.015 rem/mCi. On the basis of the pharmacokinetics, biodistribution and internal radiation dosimetry information obtained in this study, a diagnostic phase I clinical trial with 99mTc-labeled humanized MAb R3 conjugate in patients should be supported.

Clomipramine test: serum level determination in three groups of psychiatric patients.

Concentrations of clomipramine, a specific and potent serotonin uptake inhibitor, are measured in 67 psychiatric patients and 12 normal volunteers. The psychiatric patients are grouped according to the DSM III R criteria namely; pathological gamblers, obsessive compulsives and sufferers of panic disorders. Before and 30, 60, 90 and 120 min after an intravenous infusion of the drug (12.5 mg in 10 min), serum samples are collected to evaluate the concentrations of cortisol, prolactine and growth hormone. Simultaneously the clomipramine concentration of these samples is determined and these results only are reported in this communication. Very different drug concentrations are observed in individual patients receiving the same amount of drug, indicating a substantial inter-individual variability of drug metabolism. No statistical differences (Newman-Keules test) between the clomipramine concentrations from the patients of the three psychiatric groups and the normal group are observed. Neither are statistical correlations observed when clomipramine concentrations from all individuals (n = 79) are related with the age, sex or consumer behaviour (cigarette smoking, alcohol and coffee intakes) of the patients.

Incidencia de Clostridium difficile y otros agentes en pacientes con diarrea / Incidence of Clostridium difficile and other agents in diarrheic patients

Se pretende evaluar si el Clostridium difficile es un agente productor de diarrea, para lo cual se investigó las heces de 95 niños con diarrea y 26 sin diarrea, atendidos en el Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera", San José, Costa Rica. El estudio tuvo una duración de 4 meses. Simultáneamente, se hizo un estudio sobre otros agentes etiológicos en estas excretas. C. difficile se aisló en un 8.4 por ciento en niños con diarrea y en un 7.7 por ciento en muestras normales. La mayor incidencia fue para Campylobacter fetus sp. jejuni con un 25.8 por ciento en muestras diarreicas y un 3.8 por ciento en niños sin diarrea, seguidamente se ubicó Escherichia coli enteropatógena con 8.4 y 3.8 por ciento en niños con y sin diarrea respectivamente. Se discuten los aspectos clínicos y de laboratorio de los niños que cultivaron C. difficile. Se concluye que puede ser un agente productor de diarrea, pero que hacen falta más estudios sobre este tema

Monitoring aminophylline therapy using Jusko's dosage guidelines.

Treatment with aminophylline, according to the nomogram published by Jusko and coworkers, was monitored in 13 patients suffering from acute exacerbations of COPD. After 24 h of therapy, the clinical state, the pO2 and the pCO2 values were markedly improved. Theophylline plasma concentrations were maintained within the therapeutic range. A slight but noticeable increase of drug serum levels during therapy could be related to changes in the arterial pH; the implications of this finding are discussed.

Alteracion del rol sexual en ninos. / Change in sex role in children

Se estudiaron 10 pacientes de sexo masculino, cuyas edades fluctuaban entre los 6 anos y los 13 anos, los que fueron remitidos al Servicio de Neuropsiquiatria Infantil-Adolescente del Area Occidente por conducta afeminada o por otras causas, descubriendose en estos ultimos en el curso de la anamnesis este tipo de sintomatologia. Se hace un analisis de la edad de comienzo de los sintomas, de las caracteristicas de estos (rechazo por juegos y companeros de sexo masculino, preferencia por actividades sedentarias, con ninas o solos, etc.) y de la apariencia externa de estos ninos. Se pone hincapie en la descripcion de ciertas caracteristicas de personalidad en estos pacientes, asi como de su contexto familiar. Se resena brevemente su evolucion y tratamiento. Finalmente, en las conclusiones se recalca la importancia del diagnostico y tratamiento precoz en estos casos, a fin de evitar las alteraciones de la sexualidad adulta, lo que parece altamente probable si se dejan evolucionar a su suerte

Thyroid carcinoma and Cushing's syndrome. A report of two cases with a review of the common features of the "non-endocrine" tumours associated with Cushing's syndrome.

Two cases of thyroid carcinoma and Cushing's syndrome are reported. Nine other previously published cases of this association are reviewed: in one the thyroid tumour was described as medullary, in two as papillary, and in the other six as anaplastic, undifferentiated, atypical, or solid carcinoma. Both of our own cases were medullary carcinomas of the thyroid, and on reviewing the histology of five of the other cases all proved to be medullary carcinoma with identifiable amyloid in the stroma. A consideration of the temporal relationships of the development of the carcinoma and of Cushing's syndrome suggested that in the two cases with papillary carcinoma these conditions could have been unrelated, but that in eight of the nine cases with medullary carcinoma there was evidence that thyroid carcinoma was present at the time of diagnosis of Cushing's syndrome. The other main groups of the so-called ;non-endocrine' tumours associated with Cushing's syndrome are briefly reviewed, and evidence that a surprising number of these cases are related to carcinoid tumours is put forward. Medullary carcinoma of the thyroid is also probably related to this group of tumours. It is suggested that the great majority of the tumours associated with Cushing's syndrome are derived from cells of foregut origin which are endocrine in nature. In neoplasms derived from these cells the polypeptide hormone may well be imperfectly formed, and possess an amino-acid sequence in common with ACTH or other biologically active polypeptides.