Incidence and risk factors of urinary tract infection in very low birth weight infants.

OBJECTIVES: To describe the incidence and associated risk factors of urinary tract infection (UTI) in very low birth weight (VLBW) infants and to determine the value of diagnostic imaging studies after the first UTI episode before discharge from the neonatal intensive care unit (NICU). METHODS: VLBW infants born during 2003-2012 were reviewed for UTI. In a nested case-control study, potential risk factors of UTI were compared between infants with UTI (cases) versus birth weight and gestational age matched controls. Renal ultrasonography (USG) and voiding cystourethrography (VCUG) results were reviewed in cases. RESULTS: During the study period, 54.7% of urine culture specimens were collected by sterile methods. 3% (45/1,495) of VLBW infants met the study definition for UTI. UTI was diagnosed at mean postnatal age of 33.1±22.9 days. There was no significant difference in gender, ethnicity, antenatal steroid exposure, blood culture positive sepsis, ionotropic support, respiratory support and enteral feeding practices between cases and controls. Cases had a significantly higher cholestasis compared to controls (22% vs. 9% ; p = 0.03). However, cholestasis was not a significant predictor of UTI in the adjusted analysis [adjusted OR 2.38 (95% CI 0.84 to 6.80), p = 0.11]. Cases had higher central line days, parenteral nutrition days, total mechanical ventilation days, chronic lung disease, and length of stay compared to controls. Renal USG was abnormal in 37% and VCUG was abnormal in 17% of cases. CONCLUSIONS: The incidence of UTI in contemporary VLBW infants is relatively low compared to previous decades. Since no significant UTI predictors could be identified, urine culture by sterile methods is the only reliable way to exclude UTI. The majority of infants with UTI have normal renal anatomy. UTI in VLBW infants is associated with increased morbidity and length of stay.

Inflammatory bowel disease: perspectives from cingulate cortex in the first brain.

The article by Agostini et al. (2013) in this issue of Neurogastroenterology and Motility evaluated patients with Crohn's disease (CD) for volumetric changes throughout the brain. They observed decreased gray matter volumes in dorsolateral prefrontal cortex and anterior midcingulate cortex (aMCC) and disease duration was negatively correlated with volumes in subgenual anterior cingulate (sACC), posterior MCC (pMCC), ventral posterior cingulate (vPCC), and parahippocampal cortices. As all patients were in remission and suffered from ongoing abdominal pain, this study provides a critical link between forebrain changes and abdominal pain experience independent of active disease and drug treatment. The aMCC has a role in feedback-mediated decision making and there are specific cognitive tasks that differentiate aMCC and pMCC that can be used to evaluate defects in CD. The sACC is an important area as it has impaired functions in major depression. As depressive symptoms are a feature in a subset of patients with active inflammatory diseases including IBD, treatment targeting this subregion should prove efficacious. Finally, vPCC has a role in ongoing self-monitoring of the personal relevance of sensory stimuli including visceral signals via sACC. This pathway may be interrupted by vPCC atrophy in CD. Cingulate atrophy in CD leads to targeting chronic pain and psychiatric symptoms via cingulate-mediated therapies. These include psychotherapy, guided imagery and relaxation training, analgesic dosages of morphine or antidepressants, and hypnosis. Thus, a new generation of novel treatments may emerge from drug and non-traditional therapies for CD in this formative area of research.

Increased activation in cingulate cortex in conversion disorder: what does it mean?

Conversion disorder is one of the terms used to describe various psychosomatic neurological symptoms that are thought to originate from a psychological conflict. Psychological stressors can usually be identified but appear to be almost similar to the severity of psychological stress in non-psychosomatic neurological disorders. Recent neuroimaging research provides one rather robust finding of increased activation in the anterior cingulate gyrus. This activation has been explained as a reflection of 'active inhibition' or 'self-monitoring' but its meaning in conversion disorder still remains mysterious. In this paper, current theories are re-examined from a neuroanatomical point of view.

Categories of placebo response in the absence of site-specific expectation of analgesia.

Experimental placebo analgesia is induced by building an expectation of reduced pain in a specific body part, usually using an inert cream in the guise of a local anaesthetic in conjunction with conditioning. We investigated non-site-specific placebo analgesia by conditioning subjects to expect the anaesthetic cream on one arm, without specifying if they will definitely receive the cream, or to which arm it might be applied. Painful heat pulses (150 ms) from a CO2 laser were delivered randomly to both arms. A treatment group (n=24) underwent three experimental blocks (pre-cream, conditioning after cream, and post-conditioning). During the conditioning block, the intensity of the stimulus was reduced on one arm only. In the post-conditioning block it was returned to the painful level. We evaluated the change of intensity rating post-conditioning compared to the pre-cream block. In contrast to a control group (n=16), the treatment group reported a significant reduction in intensity ratings (F(1,38)=12.1; p=0.001). In the treatment group, we observed a range of placebo responses: unilateral responders (33.3%), subjects with a placebo response in the conditioned arm only; bilateral responders (33.3%), subjects reporting reduction in the intensity ratings in both arms, and non-responders, whose intensity ratings were not influenced by conditioning. We discuss these responses in terms of different levels of expected analgesia, facilitated by the absence of a site-specific focus for the treatment. We suggest this allowed the individuals suggestibility to influence their assessment of the pain experience by combining different levels of expectation with the information from the actual pain stimulus.

The Multi-Source Interference Task: validation study with fMRI in individual subjects.

Dorsal anterior cingulate cortex (dACC) plays critical roles in cognitive processing, but group-averaging techniques have generally been required to obtain significant dACC activation in functional neuroimaging studies. Development of a task that reliably and robustly activates dACC within individuals is needed to improve imaging studies of neuropsychiatric disorders and localization of dACC in normal volunteers. By combining sources of cognitive interference (Stroop, Eriksen and Simon) with factors known to increase dACC activity, the Multi-Source Interference Task (MSIT) maximally taxes dACC, making it possible to reliably activate dACC within individuals using functional magnetic resonance imaging (fMRI). In this study, eight normal adult volunteers performed the MSIT during fMRI. We compared fMRI responses and performance data between interference and control trials. Significant dACC activation (P < 1.7 x 10(-4)) was observed in all eight individuals and in the group-averaged fMRI data. In addition to dACC activation, group data also showed activation of presumably networked regions including dorsolateral prefrontal, premotor, and parietal cortices. The MSIT's reaction time interference effect (overall mean 312 +/- 61 ms) was up to 10 times greater than that of its component predecessors and temporally stable over hundreds of trials. The robustness, reliability and stability of the neuroimaging and performance data should make the MSIT a useful task with which to study normal human cognition and psychiatric pathophysiology.

Colocalization of mu-opioid receptors and activated G-proteins in rat cingulate cortex.

Anterior cingulate cortex (ACC) has a role in pain processing, however, little is known about opioid system organization and actions. This rodent study defines opioid architecture in the perigenual and midcingulate divisions of ACC, relates mu-opioid receptor binding and G-protein activation, and localizes such binding to afferent axons with knife-cut lesions and specifically to noradrenergic terminals with immunotoxin lesions (anti-dopamine beta-hydroxylase-saporin; anti-DBH-saporin). [(3)H]Tyr-D-AlaGly-MePhe-Gly-ol (DAMGO) binding was highest in perigenual areas 32 and 24 with a peak in layer I. Midcingulate area 24' and posterior cingulate area 29 had overall lower binding in each layer. In contrast, DAMGO-stimulated [(35)S]guanosine-5'-O-(gamma-thio)-triphosphate (GTPgammaS) binding in area 24' was similar to that in area 24, whereas area 29 had low and homogeneous binding. Undercut lesions reduced [(3)H]DAMGO binding in all layers with the greatest loss in layer I (-65%), whereas DAMGO-stimulated [(35)S]GTPgammaS binding losses occurred in only layers I-III. Anti-DBH-saporin reduced [(3)H]DAMGO binding in layer I of area 24; DAMGO-stimulated [(35)S]GTPgammaS binding was unchanged in areas 24' and 29. Correlation analysis of receptor and G-protein activation before and after undercut lesions suggested there were a greater number of DAMGO receptor sites for each G-protein on axons, than on somata and proximal dendrites. Finally, perigenual and midcingulate cortices have different opioid architectures due to a higher proportion of mu-opioid receptors expressed by afferent axons in areas 24 and 32.

Cytology of human caudomedial cingulate, retrosplenial, and caudal parahippocampal cortices.

Brodmann showed areas 26, 29, 30, 23, and 31 on the human posterior cingulate gyrus without marking sulcal areas. Histologic studies of retrosplenial areas 29 and 30 identify them on the ventral bank of the cingulate gyrus (CGv), whereas standardized atlases show area 30 on the surface of the caudomedial region. This study evaluates all areas on the CGv and caudomedial region with rigorous cytologic criteria in coronal and oblique sections Nissl stained or immunoreacted for neuron-specific nuclear binding protein and nonphosphorylated neurofilament proteins (NFP-ir). Ectosplenial area 26 has a granular layer with few large pyramidal neurons below. Lateral area 29 (29l) has a dense granular layer II-IV and undifferentiated layers V and VI. Medial area 29 (29m) has a layer III of medium and NFP-ir pyramids and a layer IV with some large, NFP-ir pyramidal neurons that distinguish it from areas 29l, 30, and 27. Although area 29m is primarily on the CGv, a terminal branch can extend onto the caudomedial lobule. Area 30 is dysgranular with a variable thickness layer IV that is interrupted by large NFP-ir neurons in layers IIIc and Va. Although area 30 does not appear on the surface of the caudomedial lobule, a terminal branch can form less that 1% of this gyrus. Area 23a is isocortex with a clear layer IV and large, NFP-ir neurons in layers IIIc and Va. Area 23b is similar to area 23a but with a thicker layer IV, more large neurons in layer Va, and a higher density of NFP-ir neurons in layer III. The caudomedial gyral surface is composed of areas 23a and 23b and a caudal extension of area 31. Although posterior area 27 and the parasubiculum are similar to rostral levels, posterior area 36' differs from rostral area 36. Subregional flat maps show that retrosplenial cortex is on the CGv, most of the surface of caudomedial cortex is areas 23a, 23b, and 31, and the retrosplenial/parahippocampal border is at the ventral edge of the splenium. Thus, Brodmann's map understates the rostral extent of retrosplenial cortex, overstates its caudoventral extent, and abridges the caudomedial extent of area 23.

Hypersexuality and hemiballism due to subthalamic infarction.

OBJECTIVE: A 70-year-old right-handed man presented with a subthalamic infarction followed by persistent hypersexuality and hemiballism. A lacunar infarction 1 cm in diameter was observed on magnetic resonance imaging. We hypothesized that metabolic abnormalities would be detected in cortical areas related to his neurobehavioral symptoms. BACKGROUND: Statistical validation of the regional metabolic changes that may relate to neuropsychiatric symptoms has been elusive. Relating metabolic changes to neuropsychiatric symptoms is especially important in unique neurobehavioral cases. METHOD: Quantitative fluorodeoxyglucose positron emission tomography was obtained for a single-subject comparison with scans from 60 healthy subjects. RESULTS: Substantial glucose hypometabolism (p <0.001, uncorrected; [df = 56]) was identified in the subthalamic nucleus at the site of the lacunar infarction. Hypermetabolism (p <0.01) was identified within the basal forebrain and temporal lobes, anterior cingulate and medial prefrontal cortices (areas previously associated with hypersexuality), and striatum (p <0.001) ipsilateral to the stroke (areas known to relate to hemiballism). CONCLUSIONS: Single-subject statistical parametric mapping may improve our understanding of unique neurobehavioral cases.

Aortic dissection in young patients with chronic hypertension.

We describe four patients aged 14 to 21 years who developed acute aortic dissection. In three of the four patients, the course was fatal, despite aggressive medical and surgical intervention. All four patients had sustained systemic hypertension related to chronic renal insufficiency. The patients had no other identifiable risk factors for aortic dissection, including congenital cardiovascular disease, advanced atherosclerosis, vasculitis, trauma, pregnancy, or family history of aortic dissection. Although aortic dissection is rare in individuals younger than 40 years of age, young patients with sustained systemic hypertension are at increased risk for this serious and often fatal condition. Physicians must be aware of this rare complication of hypertension and consider aortic dissection in the differential diagnosis of unusual chest, abdominal, and back pain in hypertensive children, adolescents, and young adults.

Multivariate analysis of laminar patterns of neurodegeneration in posterior cingulate cortex in Alzheimer's disease.

Posterior cingulate cortex is the site of earliest reductions in glucose metabolism and qualitatively different laminar patterns of neurodegeneration in Alzheimer's disease (AD). This study used multivariate analyses of area 23 in 72 cases of definite AD to assess relationships between laminar patterns of neurodegeneration, neurofibrillary tangle (NFT) and senile plaque (SP) densities, age of disease onset and duration, and apolipoprotein E (ApoE) genotype. No age-related changes in neurons occurred over four decades in 17 controls and regression analysis of all AD cases showed no relationships between neuron, SP, and tau-immunoreactive NFT densities. Principal components analysis of neurons in layers III-Va and eigenvector projections showed five subgroups. The subgroups were independent because each had a full range of disease durations and qualitatively different laminar patterns in degeneration suggested disease subtypes (ST). Cases with most severe neuron losses (STSevere) had an early onset, most SP, and highest proportion of ApoE epsilon4 homozygotes. Changes in the distribution of NFT were similar over disease course in two subtypes and NFT did not account for most neurodegeneration. In STII-V with moderate neuron loss in most layers, cases with no NFT had a disease duration of 3.5 +/- 0.9 years (mean +/- SEM), those with most in layers IIIc or Va had a duration of 7.3 +/- 1 years, and those with most in layers II-IIIab had a duration of 12.1 +/- 1 years. In STSevere, cases with highest NFT densities in layers II-IIIab also were late stage. Finally, epsilon4 homozygotes were most frequent in STSevere, but four statistical tests showed that this risk is not directly involved in neurodegeneration. In conclusion, multivariate pattern recognition shows that AD is composed of independent neuropathological subtypes and NFT in area 23 do not account for most neuron losses.

PCR-based apolipoprotein E genotype analysis from archival fixed brain.

A technique is described for determining the apolipoprotein E genotype (apo E; alleles epsilon2, epsilon3, or epsilon4) from tissues which have been fixed with 4-10% formaldehyde and archived. The procedure requires efficient extraction and exhaustive purification of DNA from the fixed tissue. Because the fixation process renders the DNA largely crosslinked and/or sheared (therefore unsuitable for traditional analysis), a nested polymerase chain reaction (PCR) is employed (using two apo E gene specific primer pairs) to specifically amplify the polymorphic region of the gene. The genotype was then determined using previously reported HhaI polymorphisms that occur as a direct result of the variant codons responsible for the three alleles. This protocol permitted the successful genotyping of 90% (34 out of 38) of the archived brain samples from Alzheimer's disease (AD) patients. These samples included such extremes as a sample that had been stored for 12 years in formalin. This procedure permits the retrospective analysis of samples that had been processed and stored well before the original characterization of apo E alleles as risk factors in AD. Finally, this approach is readily adapted to the analysis of any gene of interest, whether by restriction fragment length polymorphism or direct amplicon DNA sequencing. It is also a very robust assay for less stringent conditions such as DNA isolated from whole blood or frozen tissue.

Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex.

Investigations of pain using functional imaging techniques have revealed an extensive central network associated with nociception. This network includes the thalamus, insula, prefrontal cortex and anterior cingulate cortex (ACC) as well as the somatosensory cortices. Positron emission tomography (PET) of regional cerebral blood flow (rCBF) has demonstrated activation of the ACC during cognitively challenging tasks such as the Stroop interference task and divided attention. One interpretation of this research is that ACC is involved in the general features of attention and that it does not play a specific role in pain processing per se. Three-dimensional PET imaging provides a method for assessments of rCBF in a single individual during multiple tasks. In addition, coregistration of PET and magnetic resonance (MR) images allows for better localisation of the PET signals so that differences in cortical activation sites can be more accurately determined. This approach was used to assess rCBF during the experience of pain by subtracting images collected during heat from those during noxious heat stimulation. Two regions of the ACC had elevated rCBF, one in the perigenual region and one in the mid-rostrocaudal region (i.e. midcingulate cortex). During the execution of the Stroop task, the group result showed the midcingulate region overlapping with the site seen during the experience of pain. This group result, however, was not confirmed in the individual subject analysis, which revealed widespread and independent areas of ACC response to pain and Stroop. It is concluded that the ACC contributes to multiple cognitive procedures. It is inadequate to describe the primary contribution of ACC to pain processing as "attention" because it is unlikely that the multiple small and independent activation sites produced by pain and Stroop subserve attentive processing throughout the brain.

Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.

The synthesis and secretion of factor H, a regulatory protein of the complement system, were studied in skin fibroblasts from an H-deficient child who has chronic hypocomplementemic renal disease. In normal fibroblasts, factor H transcripts of 4.3 and 1.8 kilobase pairs (kb) encode a 155-kDa protein containing short consensus repeat (SCR) domains 1-20 and a 45-kDa protein which contains SCRs 1-7, respectively. The patient's fibroblasts expressed normal amounts of the 4.3- and 1.8-kb messages constitutively and after tumor necrosis factor-alpha/interferon-gamma stimulation. Lysates of [35S]methionine-labeled fibroblasts from the patient contained the 155- and 45-kDa H polypeptides, but secretion of the 155-kDa protein was blocked; the 45-kDa protein was secreted with normal kinetics. The patient's plasma lacked the 155-kDa protein but contained the small form of H. Moreover, in fibroblasts the retained 155-kDa factor H protein was not degraded, even after 12 h. Immunoflourescent staining and confocal microscopic imaging of the patient's fibroblasts indicated that factor H was retained in the endoplasmic reticulum. Sequence analysis of reverse transcription-polymerase chain reaction products (the entire coding region) and genomic DNA revealed a T1679C substitution on one allele and a G2949A substitution on the other (C518R mutation in SCR 9 and C991Y mutation in SCR 16, respectively). Both mutations affect conserved cysteine residues characteristic of SCR modules and therefore predict profound changes in the higher order structure of the 155-kDa factor H protein. These data provide the first description of a molecular mechanism for factor H deficiency and yield important insights into the normal secretory pathway for this and other plasma proteins with SCR motifs.

Neurofilament and calcium-binding proteins in the human cingulate cortex.

Functional imaging studies of the human brain have suggested the involvement of the cingulate gyrus in a wide variety of affective, cognitive, motor, and sensory functions. These studies highlighted the need for detailed anatomic analyses to delineate its many cortical fields more clearly. In the present study, neurofilament protein, and the calcium-binding proteins parvalbumin, calbindin, and calretinin were used as neurochemical markers to study the differences among areas and subareas in the distributions of particular cell types or neuropil staining patterns. The most rostral parts of the anterior cingulate cortex were marked by a lower density of neurofilament protein-containing neurons, which were virtually restricted to layers V and VI. Immunoreactive layer III neurons, in contrast, were sparse in the anterior cingulate cortex, and reached maximal densities in the posterior cingulate cortex. These neurons were more prevalent in dorsal than in ventral portions of the gyrus. Parvalbumin-immunoreactive neurons generally had the same distribution. Calbindin- and calretinin-immunoreactive nonpyramidal neurons had a more uniform distribution along the gyrus. Calbindin-immunoreactive pyramidal neurons were more abundant anteriorly than posteriorly, and a population of calretinin-immunoreactive pyramidal-like neurons in layer V was found largely in the most anterior and ventral portions of the gyrus. Neuropil labeling with parvalbumin and calbindin was most dense in layer III of the anterior cingulate cortex. In addition, parvalbumin-immunoreactive axonal cartridges were most dense in layer V of area 24a. Calretinin immunoreactivity showed less regional specificity, with the exception of areas 29 and 30. These chemoarchitectonic features may represent cellular reflections of functional specializations in distinct domains of the cingulate cortex.

Tyrosinase mRNA is expressed in human substantia nigra.

Dopamine acts, under appropriate conditions, as a selective neurotoxin. This toxicity is attributed to the autoxidation of the neurotransmitter into a reactive quinone that covalently modifies cellular macromolecules (i.e. proteins and nucleic acids). The oxidation of the catecholamine to a quinone is greatly accelerated by the enzyme tyrosinase. There is controversy, however, as to whether or not tyrosinase is expressed in human brain. In the present study, RT-PCR was utilized to demonstrate the presence of tyrosinase mRNA in post-mortem human brain tissues. Using gene-specific amplification primers, specific tyrosinase amplicons were detected following analysis of RNA from substantia nigra of four individuals. Analysis of cerebellar RNA from the same individuals produced no amplification products. Control reactions performed in the absence of reverse transcriptase failed to generate PCR products for any tissue tested. Three amplicons were subjected to direct DNA sequencing and all proved to be identical with tyrosinase sequences, thus obviating the possibility of amplification of a related gene. It is clear, therefore, that the tyrosinase gene is expressed in the human substantia nigra, lending support to previous studies describing tyrosinase-like activity and immunoreactive protein in the brain. This enzyme could be central to dopamine neurotoxicity as well as contribute to the neurodegeneration associated with Parkinson's disease.