Vulnerability of cholecystokinin-expressing GABAergic interneurons in the unilateral intrahippocampal kainate mouse model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is characterized by recurrent spontaneous seizures and behavioral comorbidities. Reduced hippocampal theta oscillations and hyperexcitability that contribute to cognitive deficits and spontaneous seizures are present beyond the sclerotic hippocampus in TLE. However, the mechanisms underlying compromised network oscillations and hyperexcitability observed in circuits remote from the sclerotic hippocampus are largely unknown. Cholecystokinin (CCK)-expressing basket cells (CCKBCs) critically participate in hippocampal theta rhythmogenesis, and regulate neuronal excitability. Thus, we examined whether CCKBCs were vulnerable in nonsclerotic regions of the ventral hippocampus remote from dorsal sclerotic hippocampus using the intrahippocampal kainate (IHK) mouse model of TLE, targeting unilateral dorsal hippocampus. We found a decrease in the number of CCK+ interneurons in ipsilateral ventral CA1 regions from epileptic mice compared to those from sham controls. We also found that the number of boutons from CCK+ interneurons was reduced in the stratum pyramidale, but not in other CA1 layers, of ipsilateral hippocampus in epileptic mice, suggesting that CCKBCs are vulnerable. Electrical recordings showed that synaptic connectivity and strength from surviving CCKBCs to CA1 pyramidal cells (PCs) were similar between epileptic mice and sham controls. In agreement with reduced CCKBC number in TLE, electrical recordings revealed a significant reduction in amplitude and frequency of IPSCs in CA1 PCs evoked by carbachol (commonly used to excite CCK+ interneurons) in ventral CA1 regions from epileptic mice versus sham controls. These findings suggest that loss of CCKBCs beyond the hippocampal lesion may contribute to hyperexcitability and compromised network oscillations in TLE.

The critical role of persistent sodium current in hippocampal gamma oscillations.

Gamma network oscillations in the brain are fast rhythmic network oscillations in the gamma frequency range (~30-100 Hz), playing key roles in the hippocampus for learning, memory, and spatial processing. There is evidence indicating that GABAergic interneurons, including parvalbumin-expressing basket cells (PVBCs), contribute to cortical gamma oscillations through synaptic interactions with excitatory cells. However, the molecular, cellular, and circuit underpinnings underlying generation and maintenance of cortical gamma oscillations are largely elusive. Recent studies demonstrated that intrinsic and synaptic properties of GABAergic interneurons and excitatory cells are regulated by a slowly inactivating or non-inactivating sodium current (i.e., persistent sodium current, INaP), suggesting that INaP is involved in gamma oscillations. Here, we tested whether INaP plays a role in hippocampal gamma oscillations using pharmacological, optogenetic, and electrophysiological approaches. We found that INaP blockers, phenytoin (40 µM and 100 µM) and riluzole (10 µM), reduced gamma oscillations induced by optogenetic stimulation of CaMKII-expressing cells in CA1 networks. Whole-cell patch-clamp recordings further demonstrated that phenytoin (100 µM) reduced INaP and firing frequencies in both PVBCs and pyramidal cells without altering threshold and amplitude of action potentials, but increased rheobase in both cell types. These results suggest that INaP in pyramidal cells and PVBCs is required for hippocampal gamma oscillations, supporting a pyramidal-interneuron network gamma model. Phenytoin-mediated modulation of hippocampal gamma oscillations may be a mechanism underlying its anticonvulsant efficacy, as well as its contribution to cognitive impairments in epilepsy patients.

Group I metabotropic glutamate receptors generate two types of intrinsic membrane oscillations in hippocampal oriens/alveus interneurons.

GABAergic interneurons in the hippocampus are critically involved in almost all hippocampal circuit functions including coordinated network activity. Somatostatin-expressing oriens-lacunosum moleculare (O-LM) interneurons are a major subtype of dendritically projecting interneurons in hippocampal subregions (e.g., CA1), and express group I metabotropic glutamate receptors (mGluRs), specifically mGluR1 and mGluR5. Group I mGluRs are thought to regulate hippocampal circuit functions partially through GABAergic interneurons. Previous studies suggest that a group I/II mGluR agonist produces slow supra-threshold membrane oscillations (<0.1 Hz), which are associated with high-frequency action potential (AP) discharges in O-LM interneurons. However, the properties and underlying mechanisms of these slow oscillations remain largely unknown. We performed whole-cell patch-clamp recordings from mouse interneurons in the stratum oriens/alveus (O/A interneurons) including CA1 O-LM interneurons. Our study revealed that the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced slow membrane oscillations (<0.1 Hz), which were associated with gamma frequency APs followed by AP-free perithreshold gamma oscillations. The selective mGluR1 antagonist (S)-(+)-α-Amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) reduced the slow oscillations, and the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) partially blocked them. Blockade of nonselective cation-conducting transient receptor potential channels, L-type Ca2+ channels, or ryanodine receptors all abolished the slow oscillations, suggesting the involvement of multiple mechanisms. Our findings suggest that group I mGluR activation in O/A interneurons may play an important role in coordinated network activity, and O/A interneuron vulnerability to excitotoxicity, in disease states like seizures, is at least in part due to an excessive rise in intracellular Ca2+.

Cell Type-specific Intrinsic Perithreshold Oscillations in Hippocampal GABAergic Interneurons.

The hippocampus plays a critical role in learning, memory, and spatial processing through coordinated network activity including theta and gamma oscillations. Recent evidence suggests that hippocampal subregions (e.g., CA1) can generate these oscillations at the network level, at least in part, through GABAergic interneurons. However, it is unclear whether specific GABAergic interneurons generate intrinsic theta and/or gamma oscillations at the single-cell level. Since major types of CA1 interneurons (i.e., parvalbumin-positive basket cells (PVBCs), cannabinoid type 1 receptor-positive basket cells (CB1BCs), Schaffer collateral-associated cells (SCAs), neurogliaform cells and ivy cells) are thought to play key roles in network theta and gamma oscillations in the hippocampus, we tested the hypothesis that these cells generate intrinsic perithreshold oscillations at the single-cell level. We performed whole-cell patch-clamp recordings from GABAergic interneurons in the CA1 region of the mouse hippocampus in the presence of synaptic blockers to identify intrinsic perithreshold membrane potential oscillations. The majority of PVBCs (83%), but not the other interneuron subtypes, produced intrinsic perithreshold gamma oscillations if the membrane potential remained above -45 mV. In contrast, CB1BCs, SCAs, neurogliaform cells, ivy cells, and the remaining PVBCs (17%) produced intrinsic theta, but not gamma, oscillations. These oscillations were prevented by blockers of persistent sodium current. These data demonstrate that the major types of hippocampal interneurons produce distinct frequency bands of intrinsic perithreshold membrane oscillations.

Development of the sexually dimorphic nucleus of the preoptic area and the influence of estrogen-like compounds.

One of the well-defined sexually dimorphic structures in the brain is the sexually dimorphic nucleus, a cluster of cells located in the preoptic area of the hypothalamus. The rodent sexually dimorphic nucleus of the preoptic area can be delineated histologically using conventional Nissl staining or immunohistochemically using calbindin D28K immunoreactivity. There is increasing use of the bindin D28K-delineated neural cluster to define the sexually dimorphic nucleus of the preoptic area in rodents. Several mechanisms are proposed to underlie the processes that contribute to the sexual dimorphism (size difference) of the sexually dimorphic nucleus of the preoptic area. Recent evidence indicates that stem cell activity, including proliferation and migration presumably from the 3(rd) ventricle stem cell niche, may play a critical role in the postnatal development of the sexually dimorphic nucleus of the preoptic area and its distinguishing sexually dimorphic feature: a signifi-cantly larger volume in males. Sex hormones and estrogen-like compounds can affect the size of the sexually dimorphic nucleus of the preoptic area. Despite considerable research, it remains un-clear whether estrogen-like compounds and/or sex hormones increase size of the sexually dimor-phic nucleus of the preoptic area via an increase in stem cell activity originating from the 3(rd) ventricle stem cell niche.

Aneurysm-related mortality rates in the US AneuRx clinical trial.

BACKGROUND: The AneuRx (Medtronic) stent graft was approved by the FDA in September 1999. The purpose of this study was to ascertain the aneurysm-related mortality rate of a subgroup of the patient cohort from Medtronic's investigational premarket study. STUDY DESIGN: There were 931 study subjects, from 19 medical centers, who were followed for an average of 3.48 years. Abdominal aortic aneurysm (AAA)-related mortality rates were examined, using death certificates and medical records. RESULTS: The 1-month postimplant death rate was 1.61%. Not counting deaths related to the initial implant, there was an increase in the rate of AAA-related mortality after 3 years, from an average of 0.18% in the first 3 years to an average of 1.39% in years 4 and 5. CONCLUSIONS: Mortality in patients implanted with an AneuRx graft (as determined in this study) probably exceeds that of open procedure patients (based on medical literature) at some point in time, likely within 4 years after implant.

Cognitive functioning, retirement status, and age: results from the Cognitive Changes and Retirement among Senior Surgeons study.

BACKGROUND: Accurate assessment of cognitive functioning is an important step in understanding how to better evaluate both clinical and cognitive competence in practicing surgeons. As part of the Cognitive Changes and Retirement among Senior Surgeons study, we examined the objective cognitive functioning of senior surgeons in relation to retirement status and age. STUDY DESIGN: Computerized cognitive tasks measuring visual sustained attention, reaction time, and visual learning and memory were administered to both practicing and retired surgeons at annual meetings of the American College of Surgeons. Data from 168 senior surgeons aged 60 and older were compared with data from 126 younger surgeons aged 45 to 59, with performance below 1.5 standard deviations or more indicating a significant difference between the groups. RESULTS: Sixty-one percent of practicing senior surgeons performed within the range of the younger surgeons on all cognitive tasks. Seventy-eight percent of practicing senior surgeons aged 60 to 64 performed within the range of the younger surgeons on all tasks compared with 38% of practicing senior surgeons aged 70 and older. Forty-five percent of retired senior surgeons performed within the range of the younger surgeons on all tasks. No senior surgeon performed below the younger surgeons on all 3 tasks. CONCLUSIONS: The majority of practicing senior surgeons performed at or near the level of their younger peers on all cognitive tasks, as did almost half of the retired senior surgeons. This suggests that older age does not inevitably preclude cognitive proficiency. The variability in cognitive performance across age groups and retirement status suggests the need for formal measures of objective cognitive functioning to help surgeons detect changes in cognitive performance and aid in their decisions to retire.

The spectrum of arterial compression at the thoracic outlet.

OBJECTIVE: In the absence of ischemic events, arterial pathology at the thoracic outlet (TO) is rarely identified because findings of chronic arterial pathology may be masked by symptoms of neurogenic compression. This study describes the clinical presentations and significance of arterial compression at the TO. METHODS: This was a retrospective analysis of the clinical records and imaging studies of 41 patients with objective findings of arterial compression at the TO. Sixteen were diagnosed from 1990 to 2003, during which 284 patients underwent surgery for TO decompression with selective arterial imaging; 25 were diagnosed from 2003 to 2009, and 62 underwent TO surgical decompressions. RESULTS: Subclavian artery stenosis, with or without poststenotic dilatation (PSD), was found in 26 patients (63%), subclavian artery aneurysms in 12 (29%), chronic subclavian occlusion in 1(2.4%), and axillary artery compression in 2 (5%). Chronic symptoms difficult to discern from neurogenic compression were present in 27 patients (66%; 24 had subclavian stenoses or PSD, or both, 1 had subclavian occlusion, and 2 had axillary artery compression); 13 (32%) presented with acute ischemia (11 had aneurysms and 2 had PSDs), and 1 asymptomatic patient had a subclavian aneurysm. Osteoarticular anomalies were found in 27 patients (66%), including 19 cervical ribs, 4 first rib anomalies, and 4 clavicular or first rib fractures, or both. Among 27 patients with subclavian aneurysms or PSD, 21 (78%) had a bone anomaly. Arterial pathology was deemed significant in 30 patients (73%) and mild or moderate in 11 (21%). Symptoms in 23 of these patients were compatible with neurogenic compression without clinical suspicion of arterial pathology, but 13 (56%) harbored a significant arterial anomaly. CONCLUSIONS: The incidence of arterial pathology secondary to compression at the TO may be underestimated, and in the absence of obvious ischemia, significant arterial pathology may not be suspected. Two-thirds of patients with arterial compression have associated bone anomalies. Therefore, routine arterial imaging seems advisable for patients evaluated for TO syndrome in the presence of a bone anomaly at the TO or an examination that shows an arterial abnormality. In the absence of these signs, however, arterial pathology may be overlooked in patients with symptoms suggestive of neurogenic compression. Further study is needed to elucidate the incidence, natural history, and clinical relevance of arterial compression and PSD at the TO.

Historical reminiscence: origin of the Greenfield filter.

The Greenfield filter was the result of collaboration between a surgeon and a petroleum engineer. Originally it was a component of a catheter management approach to massive pulmonary embolism. Industry support allowed further technical improvements and long-term patient followup studies.

Results from the cognitive changes and retirement among senior surgeons self-report survey.

BACKGROUND: The Cognitive Changes and Retirement among Senior Surgeons (CCRASS) study suggested that although subjective cognitive awareness may play a role in surgeons' retirement decisions, self-perceived cognitive decline did not predict objective cognitive performance. This article summarizes results from all participants who completed the survey portion of the CCRASS study. STUDY DESIGN: A survey examining subjective cognitive changes, changes in caseload, involvement in new technology, and retirement decisions, was administered to 995 surgeons at annual meetings of the Clinical Congress of the American College of Surgeons between 2001 and 2006. RESULTS: Forty-five percent reported increased caseload volume and 48% reported increased caseload complexity during the previous 5 years. In addition, 75% and 73% denied any recent changes in memory recall or name recognition, respectively. Increasing age was associated with decreases in clinical caseload and complexity. The majority of respondents across all age groups reported active participation in either learning (64%) or contributing (13%) to new technology in the field. Among surgeons with no imminent plans for retirement, 58% reported that a retirement decision will be based on skill level. CONCLUSIONS: Increasing age was associated with decreases in caseload and case complexity. But a steady proportion of surgeons, even in the oldest age group, are active in new surgical innovations and challenging cases. Most reported no changes in perceived cognitive abilities. The majority of surgeons who had made no decision to retire reported that their decision will be based on skill level rather than age.

Cognitive changes and retirement among senior surgeons (CCRASS): results from the CCRASS Study.

BACKGROUND: Because individuals age cognitively at different rates, there is considerable interest in ways to assure that older surgeons have the physical and mental stamina, coordination, reaction time, and judgment to provide appropriate care. To clarify potential relationships between cognitive changes related to aging, the decision to retire, and changes in patterns of surgical practice, this study aimed to identify specific parameters of cognitive change among senior surgeons. STUDY DESIGN: Computerized cognitive tasks measuring sustained attention, reaction time, visual learning, and memory were administered to 359 surgeons at the annual meetings of the American College of Surgeons over a 6-year period. A self-report survey was also administered to assess subjective cognitive changes and the status of surgical practice and retirement decisions. RESULTS: Expected age-related cognitive decline was demonstrated on all measures, although measured reaction time was notably better than age-appropriate norms. There was a marked relationship between self-reported subjective cognitive change and retirement status, but not to changes in surgical practice. There was no notable relationship, however, between subjective cognitive change and objective cognitive measures. There were marked relationships between age and retirement decision or status and between age and changes in surgical practice. CONCLUSIONS: These results suggest that although self-perceived cognitive changes play a role in the decision to retire, they are not related to objective measures of cognitive change, and are not reliable in the decision to retire. The development of readily accessible measures of cognitive changes related to aging may serve to assist decisions either to continue surgical practice or to retire.

Form and function of vena cava filters: how do optional filters measure up?

The function of vena cava filters, preventing pulmonary embolism while maintaining caval patency, is associated with the design. Several characteristics have been reported. This report evaluates retrievable filter designs in comparison with previously marketed designs with respect to efficacy and safety. Three inferior vena cava (IVC) filters (Gunther Tulip, Bard Recovery, and the Cordis OptEase) were compared on the basis of design characteristics associated with function, shape, number of trapping levels, and fixation. Adverse events reported in the literature and to the US Food and Drug Administration Manufacturers and User Facility Device Experience Database (MAUDE) were summarized. The major differences among device types include the fixation, the volume and number of trapping levels, and the amount of metal in the IVC. The MAUDE registry reported adverse events that had been hypothesized from the analysis of in vitro and in vivo testing. The Recovery and OptEase filters had the highest number of clinically important reports. From 12 to 57% were retrieved between 3 days and 11 months. Adaptations made to facilitate retrieval led to unacceptable sequelae. The small number removed, the length of time they are left in place, and the risks associated with retrieval suggest that optional filters may not be equivalent to approved permanent devices.

Surgeons outperform normative controls on neuropsychologic tests, but age-related decay of skills persists.

BACKGROUND: The present study was undertaken to determine if psychomotor and visual-spatial abilities improve as a result of surgical training or are enhanced at baseline in those individuals choosing a surgical career. METHODS: Medical students entering a surgical field and practicing surgeons performed a series of neuropsychologic tests. Performance was compared between surgeon groups, as well as with normative aged-matched controls. RESULTS: An age-related decline was noted in the performance of all exercises, with the medical student group outperforming the midcareer surgeons, who in turn outperformed the senior surgeons. Interestingly, however, all 3 groups significantly outperformed their normative control groups on some or all tasks. CONCLUSIONS: Improved visual memory and psychomotor performance compared with normative controls appears to be present at baseline rather than resulting from surgical training. Decline in performance with age is observed, however, and this should be considered when an older surgeon is learning new visually complex procedures.

Acute venous disease: venous thrombosis and venous trauma.

Acute venous disorders include deep venous thrombosis, superficial venous thrombophlebitis, and venous trauma. Deep venous thrombosis (DVT) most often arises from the convergence of multiple genetic and acquired risk factors, with a variable estimated incidence of 56 to 160 cases per 100,000 population per year. Acute thrombosis is followed by an inflammatory response in the thrombus and vein wall leading to thrombus amplification, organization, and recanalization. Clinically, there is an exponential decrease in thrombus load over the first 6 months, with most recanalization occurring over the first 6 weeks after thrombosis. Pulmonary embolism (PE) and the post-thrombotic syndrome (PTS) are the most important acute and chronic complications of DVT. Despite the effectiveness of thromboembolism prophylaxis, appropriate measures are utilized in as few as one-third of at-risk patients. Once established, the treatment of venous thromboembolism (VTE) has been defined by randomized clinical trials, with appropriate anticoagulation constituting the mainstay of management. Despite its effectiveness in preventing recurrent VTE, anticoagulation alone imperfectly protects against PTS. Although randomized trials are currently lacking, at least some data suggests that catheter-directed thrombolysis or combined pharmaco-mechanical thrombectomy can reduce post-thrombotic symptoms and improve quality of life after acute ileofemoral DVT. Inferior vena caval filters continue to have a role among patients with contra-indications to, complications of, or failure of anticoagulation. However, an expanded role for retrievable filters for relative indications has yet to be clearly established. The incidence of superficial venous thrombophlebitis is likely under-reported, but it occurs in approximately 125,000 patients per year in the United States. Although the appropriate treatment remains controversial, recent investigations suggest that anticoagulation may be more effective than ligation in preventing DVT and PE. Venous injuries are similarly under-reported and the true incidence is unknown. Current recommendations include repair of injuries to the major proximal veins. If repair not safe or possible, ligation should be performed.