Edith Nourse Rogers Memorial Veterans Hospital

Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra-high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.13 mm isotropic resolution (on average) using customized hardware. The images were manually segmented into 13 different hippocampal substructures using a protocol specifically designed for this study; precise delineations were made possible by the extraordinary resolution of the scans. In addition to the subregions, manual annotations for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo, T1-weighted MRI scans of the whole brain (1mm resolution). The manual labels from the in vivo and ex vivo data were combined into a single computational atlas of the hippocampal formation with a novel atlas building algorithm based on Bayesian inference. The resulting atlas can be used to automatically segment the hippocampal subregions in structural MRI images, using an algorithm that can analyze multimodal data and adapt to variations in MRI contrast due to differences in acquisition hardware or pulse sequences. The applicability of the atlas, which we are releasing as part of FreeSurfer (version 6.0), is demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results show that the atlas and companion segmentation method: 1) can segment T1 and T2 images, as well as their combination, 2) replicate findings on mild cognitive impairment based on high-resolution T2 data, and 3) can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1mm) T1 data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and classification based on whole hippocampal volume (82% accuracy).

IMPORTANCE: The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. OBJECTIVE: To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. INTERVENTIONS: Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319). MAIN OUTCOMES AND MEASURES: The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. RESULTS: Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). CONCLUSIONS AND RELEVANCE: Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01206062.

The projections to the frontal cortex from the various subdivisions of the posterior parietal region in the rhesus monkey were studied by means of autoradiographic technique. The rostral superior parietal lobule (area PE) projects to the dorsal areas 4 and 6 on the lateral surface of the frontal lobe as well as to the supplementary motor area (MII) on its medial surface. The caudal area PE sends its connections to dorsal area 6 and MII. The projections from the medial parietal cortex (areas PEc and PGm) are similar to those of the superior parietal lobule but they tend to concentrate in the more rostral part of dorsal area 6, MII, and in the cingulate gyrus (area 24). The most caudal part of the medial parietal cortex also projects to area 8. The anteriormost part of the inferior parietal lobule (area PF) projects to the ventral area 6, including the caudal bank of the lower branch of the arcuate sulcus, to the ventral area 46 below the sulcus principalis, and to the frontal and pericentral opercular cortex. The middle inferior parietal lobule (areas PFG and PG) projects to the ventral part of area 46 and area 8, whilst the posteriormost inferior parietal lobule (caudal PG and area Opt) is connected with both dorsal and ventral area 46, dorsal area 8, as well as the anteriormost dorsal area 6, and the cingulate gyrus (area 24).

Abstract An investigation of the architectonic organization and intrinsic connections of the prefrontal cortex was conducted in rhesus monkeys. Cytoarchitectonic analysis indicates that in the prefrontal cortex there are two trends of gradual change in laminar characteristics that can be traced from limbic periallocortex towards isocortical areas. The stepwise change in laminar features is characterized by the emergence and gradual increase in the width of granular layer IV, by an increase in the size of pyramidal cells in layers III and V, and by a higher cell‐packing density in the supragranular layers. Myeloarchitectonic analysis reveals that the limbic areas are poorly myelinated, adjacent areas have a diffuse myelin content confined to the deep layers, and in isocortices the myelinated fibers are distributed in organized horizontal bands (of Baillarger) and a vertical plexus. Using the above architectonic criteria, we observed that one of the architectonic trends takes a radial basoventral course from the periallocortex in the caudal orbitofrontal region to the adjacent proisocortex and then to area 13. The next stage of architectonic regions includes orbital areas 12, 11, and 14, which is followed by area 10, lateral area 12, and the rostral part of ventral area 46. The last group includes the caudal part of ventral area 46 and ventral area 8. The other trend takes a mediodorsal course from the periallocortex around the rostral portion of the corpus callosum to the adjacent proisocortical areas 24, 25, and 32 and then to the medially situated isocortical areas 9, 10, and 14. The next stage includes lateral areas 10 and 9 and the rostral part of dorsal area 46. The last group includes the caudal part of dorsal area 46 and dorsal area 8. The interconnections of subdivisions of the basoventral and mediodorsal cortices were studied with the aid of anterograde and retrograde tracers. Within each trend a given area projects in two directions: to adjoining regions belonging to succeeding architectonic stages on the one hand, and to nearby regions from the preceding architectonic stage on the other. In each direction there is more than one region involved in this projection system, paralleling the radial nature of architectonic change. Periallo‐ and proisocortices have widespread intrinsic connections, whereas isocortices situated at a distance from limbic areas, such as area 8, have restricted connections. Most interconnections are limited to areas within the same architectonic trend. However, there are links between cortices from the two trends, and these seem to occur between areas that are at a similar stage of architectonic differentiation. The results suggest that there are two architectonically, and perhaps functionally, distinct axes within the prefrontal cortex. The earliest stages within each axis, which have widespread connections, may have a global role in neural processing. On the other hand, the latest stages, which have restricted connections, may have a more specific role in processes associated with the frontal lobe.

Endocytosis of the Flaviviridae viruses, hepatitis C virus, GB virus C/hepatitis G virus, and bovine viral diarrheal virus (BVDV) was shown to be mediated by low density lipoprotein (LDL) receptors on cultured cells by several lines of evidence: by the demonstration that endocytosis of these virus correlated with LDL receptor activity, by complete inhibition of detectable endocytosis by anti-LDL receptor antibody, by inhibition with anti-apolipoprotein E and -apolipoprotein B antibodies, by chemical methods abrogating lipoprotein/LDL receptor interactions, and by inhibition with the endocytosis inhibitor phenylarsine oxide. Confirmatory evidence was provided by the lack of detectable LDL receptor on cells known to be resistant to BVDV infection. Endocytosis via the LDL receptor was shown to be mediated by complexing of the virus to very low density lipoprotein or LDL but not high density lipoprotein. Studies using LDL receptor-deficient cells or a cytolytic BVDV system indicated that the LDL receptor may be the main but not exclusive means of cell entry of these viruses. Studies on other types of viruses indicated that this mechanism may not be exclusive to Flaviviridae but may be used by viruses that associate with lipoprotein in the blood. These findings provide evidence that the family of LDL receptors may serve as viral receptors.

Abstract Cortical projections to subdivisions of the cingulate cortex in the rhesus monkey were analyzed with horseradish peroxidase and tritiated amino acid tracers. These projections were evaluated in terms of an expanded cytoarchitectural scheme in which areas 24 and 23 were divided into three ventrodorsal parts, i.e., areas 24a–c and 23a–c. Most cortical input to area 25 originated in the frontal lobe in lateral areas 46 and 9 and orbitofrontal areas 11 and 14. Area 25 also received afferents from cingulate areas 24b, 24c, and 23b, from rostral auditory association areas TS2 and TS3, from the subiculum and CA1 sector of the hippocampus, and from the lateral and accessory basal nuclei of the amygdala (LB and AB, respectively). Areas 24a and 24b received afferents from areas 25 and 23b of cingulate cortex, but most were from frontal and temporal cortices. These included the following areas: frontal areas 9, 11, 12, 13, and 46; temporal polar area TG as well as LB and AB; superior temporal sulcus area TPO; agranular insular cortex; posterior parahippocampal cortex including areas TF, TL, and TH and the subiculum. Autoradiographic cases indicated that area 24c received input from the insula, parietal areas PG and PGm, area TG of the temporal pole, and frontal areas 12 and 46, Additionally, caudal area 24 was the recipient of area PG input but not amygdalar afferents. It was also the primary site of areas TF, TL, and TH projections. The following projections were observed both to and within posterior cingulate cortex. Area 29a–c received inputs from area 46 of the frontal lobe and the subiculum and in turn it projected to area 30. Area 30 had afferents from the posterior parietal cortex (area Opt) and temporal area TF. Areas 23a and 23b received inputs mainly from frontal areas 46, 9, 11, and 14, parietal areas Opt and PGm, area TPO of superior temporal cortex, and areas TH, TL, and TF. Anterior cingulate areas 24a and 24b and posterior areas 29d and 30 projected to area 23. Finally, a rostromedial part of visual association area 19 also projected to area 23. The origin and termination of these connections were expressed in a number of different laminar patterns. Most corticocortical connections arose in layer III and to a lesser extent layer V, while others, e.g., those from the cortex of the superior temporal sulcus, had an equal density of cells in both layers III and V. In one instance projections to area 24 arose almost entirely from layer V of areas TH, TL, and TF. Furthermore, although most projections terminated in layers I–III of cingulate cortex, those of the amygdala to rostral area 24 terminated in deep layer I and layer II while area Opt projections to area 23 terminated mainly in layers I, II, and IV. Four classes of cortical connections have been characterized and each may play a role in the sensorimotor functions of cingulate cortex. These include connections with sensory association and multimodal areas, projections to and from premotor area 24c, subicular termination in areas 25, 24, and 29, and intracingulate connections that may transmit sensory input to areas 24 and 23 into area 24c.

By means of autoradiographic and ablation-degeneration techniques, the intrinsic cortical connections of the posterior parietal cortex in the rhesus monkey were traced and correlated with a reappraisal of cerebral architectonics. Two major rostral-to-caudal connectional sequences exist. One begins in the dorsal postcentral gyrus (area 2) and proceeds, through architectonic divisions of the superior parietal lobule (areas PE and PEc), to a cortical region on the medial surface of the parietal lobe (area PGm). This area has architectonic features similar to those of the caudal inferior parietal lobule (area PG). The second sequence begins in the ventral post/central gyrus (area 2) and passes through the rostral inferior parietal lobule (areas PG and PFG) to reach the caudal inferior parietal lobule (area PG). Both the superior parietal lobule and the rostral inferior parietal lobule also send projections to various other zones located in the parietal opercular region, the intraparietal sulcus, and the caudalmost portion of the cingulate sulcus. Areas PGm and PG, on the other hand, project to each other, to the cingulate region, to the caudalmost portion of the superior temporal gyrus, and to the upper bank of the superior temporal sulcus. Finally, a reciprocal sequence of connections, directed from caudal to rostral, links together many of the above-mentioned parietal zones. With regard to the laminar pattern of termination, the rostral-to-caudal connections are primarily distributed in the form of cortical "columns" while the caudal-to-rostral connections are found mainly over the first cortical cell layer.

Abstract The premotor cortex (area 6) has several architectonic sectors that can be delineated on the basis of cytoarchitectonic and myeloarchitectonic features. Area 6 may be broadly subdivided into a dorsal and a ventral sector at the spur of the arcuate sulcus. Dorsal 6 lacks a granular layer IV, but ventral 6 has an emergent layer IV that separates laminae III and V. Dorsal 6 has a higher myelin content than ventral 6. Dorsal area 6 is further subdivided into a caudal and a rostral sector on the basis of the presence of large pyramidal cells in the caudal but not in the rostral sector. The rostral sector of area 6 can be subdivided into a medial region distinguished from a more laterally situated area by the presence of more compact and darkly stained cells in layers III and V. Ventral area 6 can be subdivided into an upper and lower division. The upper part has more prominent pyramidal cells in layers III and V, and a better developed outer Baillarger band and vertical plexus than the lower division. The efferent and afferent connections of area 6 were studied with anterograde and retrograde tracers. The frontal connections of dorsal area 6 are restricted to neighboring dorsal frontal regions. Only the caudal sector of dorsal area 6 is connected with the motor cortex. In contrast, ventral area 6 is not only connected with the prefrontal cortex, but also directly with the motor cortex, the parainsular gustatory area, and with somatosensory areas in the frontal operculum. The widespread connections of ventral area 6 may be related to the specialization of the head, neck, and face structures that are represented ventrally within the premotor cortex.

The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.

OBJECTIVES: Trends in severe sepsis mortality derived from administrative data may be biased by changing International Classification of Diseases, 9th Revision, Clinical Modification, coding practices. We sought to determine temporal trends in severe sepsis mortality using clinical trial data that does not rely on International Classification of Diseases, 9th Revision, Clinical Modifications coding and compare mortality trends in trial data with those observed from administrative data. DESIGN: We searched MEDLINE for multicenter randomized trials that enrolled patients with severe sepsis from 1991 to 2009. We calculated standardized mortality ratios for each trial from observed 28-day mortality of usual care participants and predicted mortality from severity-of-illness scores. To compare mortality trends from clinical trials to administrative data, we identified adult severe sepsis hospitalizations in the Nationwide Inpatient Sample, 1993-2009, using two previously validated algorithms. SETTING: In-patient. PATIENTS: Patients with severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 3,244 potentially eligible articles, we included 36 multicenter severe sepsis trials, with a total of 14,418 participants in a usual care arm. Participants with severe sepsis receiving usual care had a 28-day mortality of 33.2%. Observed mortality decreased 3.0% annually (95% CI, 0.8%-5.0%; p = 0.009), decreasing from 46.9% (standardized mortality ratio 0.94; 95% CI, 0.86-1.03) during years 1991-1995 to 29% (standardized mortality ratio 0.53; 95% CI, 0.50-0.57) during years 2006-2009 (3.0% annual change). Trends in hospital mortality among patients with severe sepsis identified from administrative data (Angus definition, 4.7% annual change; 95% CI, 4.1%-5.3%; p = 0.69 and Martin definition, 3.5% annual change; 95% CI, 3.0%-4.1%; p = 0.97) were similar to trends identified from clinical trials. CONCLUSION: Since 1991, patients with severe sepsis enrolled in usual care arms of multicenter randomized trials have experienced decreasing mortality. The mortality trends identified in clinical trial participants appear similar to those identified using administrative data and support the use of administrative data to monitor mortality trends in patients with severe sepsis.

BACKGROUND: Computed tomographic pulmonary angiography (CTPA) may improve detection of life-threatening pulmonary embolism (PE), but this sensitive test may have a downside: overdiagnosis and overtreatment (finding clinically unimportant emboli and exposing patients to harms from unnecessary treatment). METHODS: To assess the impact of CTPA on national PE incidence, mortality, and treatment complications, we conducted a time trend analysis using the Nationwide Inpatient Sample and Multiple Cause-of-Death databases. We compared age-adjusted incidence, mortality, and treatment complications (in-hospital gastrointestinal tract or intracranial hemorrhage or secondary thrombocytopenia) of PE among US adults before (1993-1998) and after (1998-2006) CTPA was introduced. RESULTS: Pulmonary embolism incidence was unchanged before CTPA (P = .64) but increased substantially after CTPA (81% increase, from 62.1 to 112.3 per 100,000; P < .001). Pulmonary embolism mortality decreased during both periods: more so before CTPA (8% reduction, from 13.4 to 12.3 per 100,000; P < .001) than after (3% reduction, from 12.3 to 11.9 per 100,000; P = .02). Case fatality improved slightly before (8% decrease, from 13.2% to 12.1%; P = .02) and substantially after CTPA (36% decrease, from 12.1% to 7.8%; P < .001). Meanwhile, CTPA was associated with an increase in presumed complications of anticoagulation for PE: before CTPA, the complication rate was stable (P = .24), but after it increased by 71% (from 3.1 to 5.3 per 100,000; P < .001). CONCLUSIONS: The introduction of CTPA was associated with changes consistent with overdiagnosis: rising incidence, minimal change in mortality, and lower case fatality. Better technology allows us to diagnose more emboli, but to minimize harms of overdiagnosis we must learn which ones matter.

Acute kidney injury (AKI) associates with higher in-hospital mortality, but whether it also associates with increased long-term mortality is unknown, particularly after accounting for residual kidney function after hospital discharge. We retrospectively analyzed data from US veteran patients who survived at least 90 d after discharge from a hospitalization. We identified AKI events not requiring dialysis from laboratory data and classified them according to the ratio of the highest creatinine during the hospitalization to the lowest creatinine measured between 90 d before hospitalization and the date of discharge. We estimated mortality risks using multivariable Cox regression models adjusting for demographics, comorbidities, medication use, primary diagnosis of admission, length of stay, mechanical ventilation, and postdischarge estimated GFR (residual kidney function). Among the 864,933 hospitalized patients in the study cohort, we identified 82,711 hospitalizations of patients with AKI. In the study population of patients who survived at least 90 d after discharge, 17.4% died during follow-up (AKI 29.8%, without AKI 16.1%). The adjusted mortality risk associated with AKI was 1.41 (95% confidence interval [CI] 1.39 to 1.43) and increased with increasing AKI stage: 1.36 (95% CI 1.34 to 1.38), 1.46 (95% CI 1.42 to 1.50), and 1.59 (95% CI 1.54 to 1.65; P < 0.001 for trend). In conclusion, AKI that does not require dialysis associates with increased long-term mortality risk, independent of residual kidney function, for patients who survive 90 d after discharge. Long-term mortality risk is highest among the most severe cases of AKI.

Abstract The cytoarchitecture and thalamic afferents of cingulate cortex were evaluated in the rhesus monkey ( Macaca mulatto ). Area 24 has three divisions of which area 24a is adjacent to the callosal sulcus and has the least laminar differentiation. Area 24b has more clearly defined layers II, III, and Va, and area 24c, which forms the lower bank of the anterior cingulate sulcus, has a particularly dense layer III. Area 23 also has three divisions, each of which has a distinct layer IV. Area 23a is adjacent to the callosal sulcus and has the thinnest layers II–IV, which have the same cell density as layers V and VI. Area 23b has the largest pyramids in layers IIIc and Va, and area 23c, in the depths of the posterior cingulate sulcus, has the broadest external and thinnest internal pyramidal layers. Finally, areas 29 and 30 are located in the posterior depths of the callosal sulcus. Two divisions of area 29 are apparent: one with a granular layer directly adjacent to layer I (area 29a–c) and another with differentiation of layers III and IV (area 29d). Area 30 has a dysgranular layer IV. Injections of the retrograde tracer horseradish peroxidase (HRP) were made into subdivisions of cingulate cortex in the monkey. Area 25 received thalamic input mainly from the midline parataenial (Pt), central densocellular (Cdc), and reuniens nuclei as well as from the dorsal parvicellular division of the mediodorsal nucleus (MDpc). A less dense projection also originated in the intralaminar parafascicular (Pf), central superior, and limitans (Li) nuclei as well as the medial division of the anterior nuclei (AM). Areas 24a and 24b received most thalamic afferents from fusiform and multipolar cells in the Cdc and Pf nuclei with fewer from the ventral anterior (VA) and MDpc and MD densocellular (MDdc) nuclei and only minor input from AM. Most input to premotor cingulate area 24c appeared to originate in VA, MDdc, and Li. Area 29 received the most dense input from nuclei traditionally associated with limbic cortex including the anteroventral (AV), anterodorsal (AD), and laterodorsal (LD) nuclei. Areas 23a and 23b, in contrast, did not receive AV, AD, or LD input, but the greatest proportion of their thalamic afferents arose in AM. Less‐pronounced input also came from the lateroposterior (LP), medial pulvinar, and MDdc nuclei. This latter nucleus projected more to area 23b than to areas 30 or 23a. Anterior medial nucleus efferents to cingulate cortex were of particular note for two reasons. First, AM projected primarily to posterior cingulate areas with area 23 receiving its principal thalamic input from AM. Second, projections to areas 30, 23a, and 23b were topographically organized with ventral areas 30 and 23a receiving from the central core of AM. While the more dorsally located area 23b received input from peripheral and medial. In light of the extensive projections of Cds, Csl, and Pf to anterior cingulate cortex, it is proposed that the midline and intralaminar thalamic nuclie be classified as part of limbic thalamus along with the anterior, LD, and MD nuclei. Furthermore, although AM projects mainly to posterior cingulate cortex, it also has light projections to area 25 and minor input to area 24. As suhc, AM is the only limbic thalamic nucleus that has such widespread projections to cingulate cortex. Finally, visually evoked activity in area 23 may be the result of projections from the LP and medial pulvinar.

This article reviews cigarette smoking in patients with psychiatric disorders (PD) and substance use disorders (SUD). Rates of smoking are approximately 23% in the U.S. population but approximately two- to four-fold higher in patients with PD and SUD. Many remaining smokers have had repeated smoking cessation failures, possibly due to the presence of co-morbid PD and SUDs. There is modest, evidence-based support for effective treatment interventions for nicotine addiction in PD and SUD. Further research is needed to increase our understanding of nicotine addiction in PD and SUD and develop more effective treatment interventions.

The projections to the frontal cortex that originate from the various areas of the superior temporal region of the rhesus monkey were investigated with the autoradiographic technique. The results demonstrated that the rostral part of the superior temporal gyrus (areas Pro, Ts1, and Ts2) projects to the proisocortical areas of the orbital and medial frontal cortex, as well as to the nearby orbital areas 13, 12, and 11, and to medial areas 9, 10, and 14. These fibers travel to the frontal lobe as part of the uncinate fascicle. The middle part of the superior temporal gyrus (areas Ts3 and paAlt) projects predominantly to the lateral frontal cortex (areas 12, upper 46, and 9) and to the dorsal aspect of the medial frontal lobe (areas 9 and 10). Only a small number of these fibers terminated within the orbitofrontal cortex. The temporofrontal fibers originating from the middle part of the superior temporal gyrus occupy the lower portion of the extreme capsule and lie just dorsal to the fibers of the uncinate fascicle. The posterior part of the superior temporal gyrus projects to the lateral frontal cortex (area 46, dorsal area 8, and the rostralmost part of dorsal area 6). Some of the fibers from the posterior superior temporal gyrus run initially through the extreme capsule and then cross the claustrum as they ascend to enter the external capsule before continuing their course to the frontal lobe. A larger group of fibers curves round the caudalmost Sylvian fissure and travels to the frontal cortex occupying a position just above and medial to the upper branch of the circular sulcus. This latter pathway constitutes a part of the classically described arcuate fasciculus.

The perfusion of rat brain with 125I-transferrin resulted in a receptor-mediated uptake of transferrin into the endothelium of the blood-brain barrier followed by its detection in the brain. During a pulse-chase experiment, 125I-transferrin accumulated in the endothelial cells during the pulse, with a decrease of this intraendothelial radioactivity during the chase associated with a concomitant increase in the nonvascular elements of the brain. The receptor-mediated movement of transferrin across the blood-brain barrier suggests that the brain may derive its iron through the transcytosis of iron-loaded transferrin across the brain microvasculature. We discuss the likelihood that aluminum and other potentially toxic heavy metals, which also bind tightly to transferrin, may enter the brain by this pathway. We also discuss the possibility that other large molecules including neuroactive peptides and neurotrophic viruses may enter the brain through a similar receptor-mediated, vesicular transcytotic route.

Retroviral vectors constructed to contain the herpes simplex virus thymidine kinase (HSV-TK) gene were used for transduction of this gene into murine sarcoma and lymphoma cells to yield sublines susceptible in vitro to the cytotoxicity of ganciclovir, a drug specifically activated by HSV-TK. In vivo, ganciclovir induced complete, durable regressions in most mice bearing transplanted HSV-TK-positive sarcomas; its efficacy against lymphomas was only marginal, possibly because of their greater instability of gene expression. The results imply the potential value of an anticancer strategy entailing the prophylactic use of retroviral vectors to create tissue mosaicism for drug sensitivity.

OBJECTIVES: To evaluate how cognitive function and divided attention affect gait in Alzheimer's disease (AD). DESIGN: Cross-sectional intervention study with subjects serving as their own controls. SETTING: Inpatient unit and outpatient clinic for patients with dementia located at a Veterans Affairs Medical Center. PARTICIPANTS: Twenty-eight patients diagnosed with probable AD. INTERVENTION: Performance of a cognitive task (repeating random digits) while walking. MEASUREMENTS: Neuropsychological measures including clock drawing, verbal fluency, and digit span were obtained along with the Clinical Dementia Rating and Mini-Mental State Examination, the measures of dementia severity. Gait speed and stride-to-stride variability of gait rhythm were measured, once during normal walking and once during dual-task walking. RESULTS: During usual walking, subjects walked slowly and with greater gait variability than older adults without AD. Gait speed was significantly reduced (P<.012) and gait variability increased with dual-task walking (P<.007). The effect on gait variability was larger than the effect on gait speed (P<.015). Executive and neuropsychological function were significantly (P<.02) associated with the increased gait variability that occurred when walking with divided attention but not with gait speed or usual, single-task walking measures of gait. CONCLUSION: Divided attention markedly impairs the ability of patients with AD to regulate the stride-to-stride variations in gait timing. This susceptibility to distraction and its effect on stride time variability, a measure of gait unsteadiness, could partially explain the predilection to falling observed in patients with dementia. The results also support the concept that persons with AD have significant impairments in the cognitive domain of attention and that locomotor function relies upon cognitive, especially executive, function.

During the last decade, there has been heated debate regarding whether compulsive sexual behaviour should be classified as a mental/behavioural disorder. Compulsive sexual behaviour disorder has been proposed for inclusion as an impulse control disorder in the ICD-111. It is characterized by a persistent pattern of failure to control intense, repetitive sexual impulses or urges, resulting in repetitive sexual behaviour over an extended period (e.g., six months or more) that causes marked distress or impairment in personal, family, social, educational, occupational or other important areas of functioning. The pattern is manifested in one or more of the following: a) engaging in repetitive sexual activities has become a central focus of the person's life to the point of neglecting health and personal care or other interests, activities and responsibilities; b) the person has made numerous unsuccessful efforts to control or significantly reduce repetitive sexual behaviour; c) the person continues to engage in repetitive sexual behaviour despite adverse consequences (e.g., repeated relationship disruption, occupational consequences, negative impact on health); or d) the person continues to engage in repetitive sexual behaviour even when he/she derives little or no satisfaction from it. Concerns about overpathologizing sexual behaviours are explicitly addressed in the diagnostic guidelines proposed for the disorder. Individuals with high levels of sexual interest and behaviour (e.g., due to a high sex drive) who do not exhibit impaired control over their sexual behaviour and significant distress or impairment in functioning should not be diagnosed with compulsive sexual behaviour disorder. The diagnosis should also not be assigned to describe high levels of sexual interest and behaviour (e.g., masturbation) that are common among adolescents, even when this is associated with distress. The proposed diagnostic guidelines also emphasize that compulsive sexual behaviour disorder should not be diagnosed based on psychological distress related to moral judgments or disapproval about sexual impulses, urges or behaviours that would otherwise not be considered indicative of psychopathology. Sexual behaviours that are egodystonic can cause psychological distress; however, psychological distress due to sexual behaviour by itself does not warrant a diagnosis of compulsive sexual behaviour disorder. Careful attention must be paid to the evaluation of individuals who self-identify as having the disorder (e.g., calling themselves “sex addicts” or “porn addicts”). Upon examination, such individuals may not actually exhibit the clinical characteristics of the disorder, although they might still be treated for other mental health problems (e.g., anxiety, depression). Additionally, individuals often experience feelings such as shame and guilt in relationship to their sexual behaviour2, but these experiences are not reliably indicative of an underlying disorder. The proposed diagnostic guidelines also assist the clinician in differentiating compulsive sexual behaviour disorder from other mental disorders and other health conditions. For example, although bipolar disorder has been found at elevated rates among individuals with compulsive sexual behaviour disorder3, sexual behaviours must be persistent and occur independently of hypomanic or manic episodes to provide a basis for a possible diagnosis of the disorder. A diagnosis of compulsive sexual behaviour disorder should not be made when the behaviour can be explained by other medical conditions (e.g., dementia) or by the effects of certain medications prescribed to treat specific medical conditions (e.g., Parkinson's disease)4 or is entirely attributable to the direct effects of illicit substances on the central nervous system (e.g., cocaine, crystal methamphetamine). Currently, there is an active scientific discussion about whether compulsive sexual behaviour disorder can constitute the manifestation of a behavioural addiction5. For ICD-11, a relatively conservative position has been recommended, recognizing that we do not yet have definitive information on whether the processes involved in the development and maintenance of the disorder are equivalent to those observed in substance use disorders, gambling and gaming6. For this reason, compulsive sexual behaviour disorder is not included in the ICD-11 grouping of disorders due to substance use and addictive behaviours, but rather in that of impulse control disorders. The understanding of compulsive sexual behaviour disorder will evolve as research elucidates the phenomenology and neurobiological underpinnings of the condition7. In the absence of consistent definitions and community-based epidemiological data, determining accurate prevalence rates of compulsive sexual behaviour disorder has been difficult. Epidemiological estimates have ranged up to 3-6% in adults8, though recent studies have produced somewhat lower estimates of 1 to 3%9. The more restrictive diagnostic requirements proposed for ICD-11 would be expected to produce lower prevalence rates. In general, men exhibit the disorder more frequently than women, although robust data examining gender differences are lacking. Additionally, higher rates of the disorder have been noted among individuals with substance use disorders. Among treatment seekers, the disorder negatively impacts occupational, relationship, physical health and mental health functioning. However, systematic data are lacking regarding the prevalence of the disorder across different populations and associated socio-cultural and socio-demographic factors, including among non-treatment seekers. Growing evidence suggests that compulsive sexual behaviour disorder is an important clinical problem with potentially serious consequences if left untreated. We believe that including the disorder in the ICD-11 will improve the consistency with which health professionals approach the diagnosis and treatment of persons with this condition, including consistency regarding when a disorder should not be diagnosed. Legitimate concerns about overpathologizing sexual behaviours have been carefully addressed in the proposed diagnostic guidelines. We posit that inclusion of this category in the ICD-11 will provide a better tool for addressing the unmet clinical needs of treatment seeking patients as well as possibly reduce shame and guilt associated with help seeking among distressed individuals. The proposed diagnostic guidelines will be tested in international multilingual Internet-based field studies using standardized case material, which will help to assess the generalizability of the construct across different regions and cultures, and clinicians’ ability to distinguish it from normal variations in sexual behaviour and from other disorders. Additional field studies in clinical settings will provide further information about the clinical utility of the proposed diagnostic guidelines for the disorder among clinical populations. Shane W. Kraus1, Richard B. Krueger2, Peer Briken3, Michael B. First2, Dan J. Stein4, Meg S. Kaplan2, Valerie Voon5, Carmita H.N. Abdo6, Jon E. Grant7, Elham Atalla8, Geoffrey M. Reed9,10 1Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA; 2Department of Psychiatry, Columbia University, College of Physicians and Surgeons and New York State Psychiatric Institute, New York, NY, USA; 3Institute for Sex Research and Forensic Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Psychiatry, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; 5Department of Psychiatry, University of Cambridge, Cambridge, UK; 6Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; 7Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA; 8Primary Care and Public Health Directorate, Ministry of Health, Manama, Bahrain; 9Department of Mental Health and Substance Abuse, World Health Organization, Geneva, Switzerland; 10Global Mental Health Program, Columbia University Medical Center, New York, NY, USA