Cognitive ageing is premature among a community sample of optimally treated people living with HIV.

OBJECTIVES: Evidence of premature cognitive ageing amongst people living with HIV (PLHIV) remains controversial due to previous research limitations including underpowered studies, samples with suboptimal antiretroviral access, varying rate of virological control, high rate of AIDS, over-representation of non-community samples, and inclusion of inappropriate controls. The current study addresses these limitations, while also considering mental health and non-HIV comorbidity burden to determine whether PLHIV showed premature cognitive ageing compared with closely comparable HIV-negative controls. METHODS: This study enrolled 254 PLHIV [92% on antiretroviral therapy; 84% with HIV RNA < 50 copies/mL; 15% with AIDS) and 72 HIV-negative gay and bisexual men [mean (SD) age = 49 (10.2) years] from a single primary care clinic in Sydney, Australia. Neurocognitive function was evaluated with the Cogstate Computerized Battery (CCB) at baseline and 6 months after. Linear mixed-effects (LME) models examined main and interaction effects of HIV status and chronological age on the CCB demographically uncorrected global neurocognitive z-score (GZS), adjusting for repeated testing, and then adjusting sequentially for HIV disease markers, mental health and comorbidities. RESULTS: HIV status and age interacted with a lower GZS (ß = -0.43, P < 0.05). Higher level of anxiety symptoms (ß = -0.11, P < 0.01), historical AIDS (ß = -0.12, P < 0.05) and historical HIV brain involvement (ß = -0.12, P < 0.05) were associated with lower GZS. CONCLUSIONS: We found a robust medium-sized premature ageing effect on cognition in a community sample with optimal HIV care. Our study supports routine screening of cognitive and mental health among PLHIV aged ≥ 50 years.

Functional Connectivity in Virally Suppressed Patients with HIV-Associated Neurocognitive Disorder: A Resting-State Analysis.

BACKGROUND AND PURPOSE: HIV-associated neurocognitive disorder still occurs despite virally suppressive combination antiretroviral therapy. In the pre-combination antiretroviral era and in patients without HIV suppression, HIV-associated neurocognitive disorder was caused by synaptodendritic injury resulting in impairment of neural networks, characterized by decreased attention, psychomotor slowing, and working memory deficits. Whether similar pathogenesis is true for HIV-associated neurocognitive disorder in the context of viral suppression is not clear. Resting-state fMRI has been shown to be efficient in detecting impaired neural networks in various neurologic illnesses. This pilot study aimed to assess resting-state functional connectivity of the brain in patients with active HIV-associated neurocognitive disorder in the context of HIV viral suppression in both blood and CSF. MATERIALS AND METHODS: Eighteen patients with active HIV-associated neurocognitive disorder (recent diagnosis with progressing symptoms) on combination antiretroviral therapy with viral suppression in both blood and CSF and 9 demographically matched control subjects underwent resting-state functional MR imaging. The connectivity in the 6 known neural networks was assessed. To localize significant ROIs within the HIV and control group, we performed a seed-based correlation for each known resting-state network. RESULTS: There were significant group differences between the control and HIV-associated neurocognitive disorder groups in the salience (0.26 versus 0.14, t = 2.6978, df = 25, P = .0123) and executive networks (0.52 versus 0.32, t = 2.2372, df = 25, P = .034). The covariate analysis with neuropsychological scores yielded statistically significant correlations in all 6 studied functional networks, with the most conspicuous correlation in salience networks. CONCLUSIONS: Active HIV-associated neurocognitive disorder in virally suppressed patients is associated with significantly decreased connectivity in the salience and executive networks, thereby making it potentially useful as a biomarker.

Pitx3-deficient aphakia mice display unique behavioral responses to psychostimulant and antipsychotic drugs.

The dorsal (A9) and ventral striatum (A10) of the midbrain mediate many of the effects of psychoactive drugs that alter emotion, cognition, and motor activity within the contexts of therapy or abuse. Although transgenic and knockout technologies have enabled development of genetic models to dissect contributions of specific dopamine (DA) receptor subtypes to psychoactive drug effects, few models exist that can distinguish contributions of A9 versus A10 circuits. Pitx3 is a transcription factor enriched in DA neurons. Aphakia (ak) mice deficient in Pitx3 show selective loss of nigrostriatal DA, while other DA pathways are relatively spared, and therefore could be a useful tool for investigating the role of this subclass of DA projections. We investigated the effects of stimulants amphetamine, apomorphine, and MK-801 and the antipsychotic drug haloperidol on behavior in ak mice. Whereas wild-type mice showed the characteristic locomotor hyperactivity in response to amphetamine (5 mg/kg) and apomorphine (4 mg/kg), these drugs caused a paradoxical suppression of locomotor hyperactivity in ak mice. MK-801 (0.2 mg/kg) induced hyperactivity was maintained in both wt and ak mice. Additionally, mutant but not wild-type mice were insensitive to the cataleptic effects of haloperidol (1 mg/kg). These studies indicate that the nigrostriatal DA circuit plays a critical role in maintaining normal responsiveness to psychotropic drugs that either stimulate or block DA neurotransmission. We propose that ak mice may represent a valuable genetic model not only to study Parkinson's disease, but also to dissect the pathophysiologic and pharmacotherapuetic mechanisms of other DA-mediated disorders such as attention-deficit hyperactivity disorder, drug abuse and schizophrenia.

Asenapine induces differential regional effects on serotonin receptor subtypes.

Asenapine, a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has high affinity for a wide range of receptors, including the serotonergic receptors 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT( 2B), 5-HT(2C), 5-HT(5A), 5-HT(6) and 5-HT( 7). We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT(1A), 5-HT(2A) and 5-HT(2C). Rats were given asenapine (0.03, 0.1 or 0.3 mg/kg) subcutaneously twice daily or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), caudate putamen, nucleus accumbens, hippocampal CA( 1) and CA(3) regions, and entorhinal cortex and processed for in-vitro receptor autoradiography. Asenapine 0.1 and 0.3 mg/kg significantly increased 5-HT(1A) binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal CA(1) region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/kg) significantly decreased 5-HT(2A) binding by a similar degree in mPFC (40%, 44%, 47%, respectively) and DFC (45%, 51%, 52%) (all P < 0.05), but did not alter 5-HT(2A) binding in the other brain regions studied. In contrast to the effects on 5-HT(1A) and 5-HT(2A) receptors, asenapine did not alter 5-HT(2C) binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine.

Diaphragmatic rupture: a frequently missed injury in blunt thoracoabdominal trauma patients.

In the US and Western Europe, trauma is the fourth most common cause of death and the leading cause of death in the population less than 45 years of age [Mullinix and Foley, J Comput Assist Tomogr 28(Suppl 1):S20-S27, 2004]. Diaphragmatic injuries occur in 0.8 to 8% of patients after blunt trauma (Gray H, The muscles of the thorax. Anatomy of the human body. Lea & Febiger, Philadelphia, 1918) and may be a predictor of severity of injury in the blunt trauma patient [Worthy et al., Radiology 194(3):885-888, 1995]. The clinical diagnosis of diaphragmatic rupture (DR) is difficult and is missed in anywhere from 7 to 66% of patients [Cantwell, Radiology 238(2):752-753, 2006]. The accurate diagnosis and prognosis of this pathology depend on a complete knowledge of the clinical and radiological presentation. Computed tomography is the imaging modality of choice in the assessment of patients with clinical or radiographic findings suggestive of DR.

Screening for cancer: evaluating the evidence.

Many patients expect to undergo screening tests for cancer. In evaluating screening procedures, physicians must take into account the known effects of lead time, length and screening biases, all of which can result in an overestimation of the benefits of screening. The gold standard by which a screening test is evaluated remains the prospective, randomized controlled trial, demonstrating reduced morbidity and mortality. The magnitude of benefit from screening is best expressed in terms of the number of patients needed to screen. This value ranges from approximately 500 to 1,100 for proven screening interventions. These concepts are illustrated by controversies in current screening recommendations for cancers of the cervix, lung, colon, breast and prostate, which together account for more than 50 percent of cancer deaths in the United States.

Association of attending physician specialty with the cesarean delivery rate in the same patient population.

BACKGROUND AND OBJECTIVES: In the context of a dramatic increase in US cesarean delivery rates over the past 30 years and explicit national goals to decrease the cesarean rate, previous retrospective studies have shown that pregnant women cared for by family physicians may be less likely to undergo cesarean delivery, compared with patients cared for by obstetricians. METHODS: We conducted a retrospective chart review of 3,560 deliveries from the family practice service of a community-based family practice residency from 1986-1995, focusing primarily on cesarean delivery rates during two periods of time. During period 1 (n = 1,063), all attending were private practice obstetricians. After a transition period, all births were attended by family medicine faculty (period 2, n = 1,346). RESULTS: The total cesarean delivery rate declined from 16.7% in period 1 to 11.1% in period 2. Repeat cesareans declined from 8.5% to 2.9%. CONCLUSIONS: In this community-based residency, a change in the specialty of the attending physician was associated with a 34% decline in the cesarean delivery rate. The observed decline in the cesarean rate could not be accounted for by any change in patient demographics or secular trends in cesarean delivery rates.

Radionuclides in the lichen-caribou-human food chain near uranium mining operations in northern Saskatchewan, Canada.

The richest uranium ore bodies ever discovered (Cigar Lake and McArthur River) are presently under development in northeastern Saskatchewan. This subarctic region is also home to several operating uranium mines and aboriginal communities, partly dependent upon caribou for subsistence. Because of concerns over mining impacts and the efficient transfer of airborne radionuclides through the lichen-caribou-human food chain, radionuclides were analyzed in tissues from 18 barren-ground caribou (Rangifer tarandus groenlandicus). Radionuclides included uranium (U), radium (226Ra), lead (210Pb), and polonium (210Po) from the uranium decay series; the fission product (137Cs) from fallout; and naturally occurring potassium (40K). Natural background radiation doses average 2-4 mSv/year from cosmic rays, external gamma rays, radon inhalation, and ingestion of food items. The ingestion of 210Po and 137Cs when caribou are consumed adds to these background doses. The dose increment was 0.85 mSv/year for adults who consumed 100 g of caribou meat per day and up to 1.7 mSv/year if one liver and 10 kidneys per year were also consumed. We discuss the cancer risk from these doses. Concentration ratios (CRs), relating caribou tissues to lichens or rumen (stomach) contents, were calculated to estimate food chain transfer. The CRs for caribou muscle ranged from 1 to 16% for U, 6 to 25% for 226Ra, 1 to 2% for 210Pb, 6 to 26% for 210Po, 260 to 370% for 137Cs, and 76 to 130% for 40K, with 137Cs biomagnifying by a factor of 3-4. These CRs are useful in predicting caribou meat concentrations from the lichens, measured in monitoring programs, for the future evaluation of uranium mining impacts on this critical food chain.

Frontobasilar blast injuries: access and treatment.

Blast injuries involving the frontobasilar region and orbit can present difficult evaluation and treatment challenges. This article presents the surgical treatment of four patients presenting with blast-type injuries involving the central periorbital region and anterior skull base. Three of these were the result of close-range gunshot wounds, and one was caused by an avulsive penetrating tree branch injury during a motor vehicle accident. All four patients underwent frontal craniotomy for exposure to repair significant intracranial injuries. Following intracranial repair of dural and brain injuries, anterior cranial fossa reconstruction was performed. In two of these patients, elective supraorbital osteotomies were performed to allow improved access to the posterior aspect of the anterior skull base. The healing period of all four patients has been without complications relative to the anterior fossa injuries.

Immunocytochemical localization of glycine in a subset of cartwheel cells of the dorsal cochlear nucleus in rats.

Glycine is an inhibitory neurotransmitter and a glutamate cofactor for N-methyl-D-aspartate (NMDA) receptors in the central nervous system. The distribution of glycine in the auditory system will therefore provide clues as to synaptic mechanisms underlying auditory signal processing. Previous studies have reported the immunocytochemical presence of glycine in the dorsal cochlear nucleus of a variety of mammals, but the specificity with respect to particular cell types has proven elusive at the light microscopic level. We sought to identify cell types in the superficial regions of the dorsal cochlear nucleus that were immunoreactive to glycine using light and electron microscopy in the rat. At the light microscopic level, glycine immunoreactivity was present in some but not all medium-sized cells in layers I and II. The somata of pyramidal and granule cells were not stained. At the electron microscopic level, using previously published ultrastructural criteria, we examined the glycine-labeled cells and determined that many but not all cartwheel cells were labeled. We also observed unlabeled unipolar brush cells, Golgi cells, and stellate cells. As some of the labeled cells could not be identified, we could not determine whether unipolar brush cells, Golgi cells or stellate cells had both labeled and unlabeled subpopulations. Our observations indicate that within the population of cartwheel cells, only a subset are glycine-immunoreactive.

Neuroimaging of fractureless transforamen magnum penetrating injury of the cerebellum.

An unusual case of penetrating injury to the cerebellum by a foreign body is described. The authors recommend plain radiographs and computed tomography to rule out fractures of the skull vault and base and the upper cervical spine, as well as to ascertain the presence and location of foreign bodies. Magnetic resonance imaging is ideal for the follow-up assessment of brain damage.

Palinopsia: a review of the literature.

The literature on palinopsia (visual perseveration) is reviewed, utilizing case reports of 46 patients who demonstrated this symptom. The most common etiologies for this symptom are space-occupying lesions, cerebral infarct, and seizure activity. The vast majority are due to central nervous system pathology occurring in the posterior (occipital or parieto-occipital) region, often in the right hemisphere. Proposed mechanisms for palinopsia are also discussed.