HSD3B1 (1245A>C) germline variant and clinical outcomes in metastatic castration-resistant prostate cancer patients treated with abiraterone and enzalutamide: results from two prospective studies.

BACKGROUND: A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide. PATIENTS AND METHODS: A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone + prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate. RESULTS: The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02-1.67, P = 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P = 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99-1.66, P = 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P = 0.997) and TTP (P = 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP. CONCLUSIONS: The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.

BACKGROUND: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. METHODS: Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. RESULTS: Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). CONCLUSION: Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.

Open darn repair vs open mesh repair of inguinal hernia: a systematic review and meta-analysis of randomised and non-randomised studies.

OBJECTIVES: To compare the outcomes of open darn repair vs open mesh repair in patients undergoing inguinal hernia repair. METHODS: We performed a systematic review and conducted a search of electronic information sources to identify all observational studies and randomised controlled trials (RCTs) investigating outcomes of open darn repair vs open mesh repair for inguinal hernias. Hernia recurrence was considered as the primary outcome measure. The secondary outcome measures included surgical site infection (SSI), haematoma, seroma, neuralgia, urinary retention, length of hospital stay, time to return to normal activities or work, testicular atrophy, operative time and chronic pain. Random or fixed effects modelling was applied to calculate pooled outcome data. RESULTS: Six RCTs, enrolling 1480 patients with 1485 hernias, and 4 observational studies, enrolling 1564 patients with 1641 hernias, were included. Meta-analysis of RCTs showed no significant difference in terms of recurrence (RD 0.00, 95% CI - 0.01 to 0.01, P = 0.86), SSI (OR 0.83, 95% CI 0.46-1.49, P = 0.52), haematoma (OR 1.21, 95% CI 0.62-2.38, P = 0.57), seroma (OR 0.83, 95% CI 0.42-1.65, P = 0.60), neuralgia (OR 1.05, 95% CI 0.29-3.73, P = 0.94), urinary retention (OR 1.44, 95% CI 0.64-3.21, P = 0.38), length of hospital stay (MD 0.09, 95% CI - 0.28 to 0.46, P = 0.63), time to return to normal activities or work (MD 0.88, 95% CI - 0.90 to 2.66, P = 0.33), testicular atrophy (RD 0.00, 95% CI - 0.02 to 0.02, P = 1.00), and operative time (MD 2.69, 95% CI - 1.75 to 7.14, P = 0.62) between the darn repair and mesh repair groups. Meta-analysis of observational studies also showed no significant difference in terms of recurrence (RD 0.00, 95% CI - 0.02 to 0.02, P = 0.99), SSI (OR 0.47, 95% CI 0.14-1.62, P = 0.23), haematoma (OR 1.07, 95% CI 0.45-2.55, P = 0.89), seroma (OR 0.12, 95% CI 0.01-2.27, P = 0.16), neuralgia (OR 0.25, 95% CI 0.05-1.21, P = 0.08), urinary retention (OR 1.53, 95% CI 0.20-11.96, P = 0.69), time to return to normal activities or work (MD 2.13, 95% CI - 2.18 to 6.44, P = 0.33), testicular atrophy (RD - 0.01, 95% CI - 0.02 to 0.01, P = 0.49), and operative time (MD - 4.76, 95% CI - 13.23 to 3.71, P = 0.27) between the two groups. The evidence was inconclusive for chronic pain. The quality of available evidence was moderate. CONCLUSIONS: Our results suggest that open darn repair is comparable with open mesh repair for inguinal hernias. Considering that consequences of mesh complications in inguinal hernia repair, albeit rare, can be significant, open darn repair provides an equally credible alternative to open mesh repair for inguinal hernias. Further studies are required to investigate patient-reported outcomes and to elicit a superior non-mesh technique.

360° virtual reality video for the acquisition of knot tying skills: A randomised controlled trial.

BACKGROUND: 360° virtual reality (VR) video is an exciting and evolving field. Current technology promotes a totally immersive, 3-dimensional (3D), 360° experience anywhere in the world using simply a smart phone and virtual reality headset. The potential for its application in the field of surgical education is enormous. The aim of this study was to determine knot tying skills taught with a 360-degree VR video compared to conventional 2D video teaching. MATERIAL AND METHODS: This trial was a prospective, randomised controlled study. 40 foundation year doctors (first year postgraduate) were randomised to either the 360-degree VR video (n = 20) or 2D video teaching (n = 20). Participants were given 15 min to watch their allocated video. Ability to tie a single handed reef knot was then assessed against a marking criteria developed for the Royal College of Surgeons, England, (RCSeng) Basic Surgical Skills (BSS) course, by a blinded assessor competent in knot tying. Each candidate then underwent further teaching using Peyton's four step model. Knot tying technique was then re-assessed. RESULTS: Knot tying scores were significantly better in the VR video teaching arm when compared with conventional (median knot score 5.0 vs 4.0 p = 0.04). When used in combination with face to face skills teaching this difference persisted (median knot score 9.5 vs 9.0 p = 0.01). More people in the VR arm constructed a complete reef knot than in the 2D arm following face to face teaching (17/20 vs 12/20). No difference between the groups existed in the time taken to construct a reef knot following video and teaching (median time 31.0s vs 30.5s p = 0.89). CONCLUSION: This study shows there is significant merit in the application of 360-degree VR video technology in surgical training, both as an independent teaching aid and when used as an adjunct to traditional face to face teaching.

Considerations for non-invasive in-flight monitoring of astronaut immune status with potential use of MEMS and NEMS devices.

The dynamics of how astronauts' immune systems respond to space flight have been studied extensively, but the complex process has not to date been thoroughly characterized, nor have the underlying principles of what causes the immune system to change in microgravity been fully determined. Statistically significant results regarding overall immunological effects in space have not yet been established due to the relatively limited amount of experimental data available, and are further complicated by the findings not showing systematically reproducible trends. Collecting in vivo data during flight without affecting the system being measured would increase understanding of the immune response process. The aims of this paper are to briefly review the current knowledge regarding how the immune system is altered in space flight; to present a group of candidate biomarkers that could be useful for in-flight monitoring and give an overview of the current methods used to measure these markers; and finally, to further establish the need and usefulness of incorporating real-time analytical techniques for in-flight assessment of astronaut health, emphasizing the potential application of MEMS/NEMS devices.

Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience.

PURPOSE: In a previously reported randomized Southeastern Cancer Study Group (SECSG) trial, three cycles of chemotherapy were found to be equivalent to four cycles in patients with favorable-prognosis germ-cell cancer. We have conducted a follow-up analysis of patients treated at Indiana University (Indianapolis, IN) to compare long-term survival between the two groups and to examine factors associated with survival. PATIENTS AND METHODS: Sixty-nine patients with minimal-stage and 49 patients with moderate-stage disseminated germ-cell tumors were randomized to either three or four courses of bleomycin, etoposide, and cisplatin (BEP) administered every 3 weeks. Median follow-up time is 10.1 years (range, 7 months to 12.6 years). Ninety-two percent of patients have an actual follow-up time of > 5 years, and 97.5% of patients have an actual follow-up time of > 3 years. RESULTS: Survival analysis shows no significant difference between the two treatment groups in terms of overall (P = .80) or disease-free (P = .93) survival. Several clinical variables were examined by univariate analysis; only serum human chorionic gonadotropin (HCG) had an impact on survival. There were two disease-related deaths in 104 patients with HCG < or = 1,000 mIU/mL and five disease-related deaths in 14 patients with HCG greater than 1,000 mIU/mL (P < .001). Ninety-eight percent (95% CI, 95.2 to 100) of patients with favorable prognosis germ-cell tumor with an initial HCG of < or = 1,000 mIU/mL are alive without evidence of disease at 5+ years. CONCLUSION: With long-term follow-up, there is no statistically significant difference in survival between three or four cycles of BEP chemotherapy in patients with favorable prognosis germ-cell carcinoma. Serum HCG elevation of greater than 1,000 mIU/mL is a significant predictor of poor outcome in patients with otherwise good-risk disease.

Effect of insulin on renal sodium handling in hypertensive rats.

Spontaneously hypertensive rats have reduced peripheral insulin sensitivity. To determine whether hypertensive rats demonstrate reduced response to the antinatriuretic effect of insulin, urinary sodium excretion was determined in hypertensive and normotensive rats (n = 7 per group) before and during euglycemic insulin administration at two infusion rates (21 milliunits/kg load and 4 milliunits/kg/min or 85 milliunits/kg load and 8 milliunits/kg/min). Hypertensive and normotensive time controls received the vehicle for insulin administration. Mean arterial pressure was greater (p less than 0.05) and inulin clearance was less (p less than 0.05) in hypertensive than normotensive rats before insulin infusion. Baseline fractional sodium excretion was not different between groups. Low dose insulin infusion reduced (p less than 0.05) fractional sodium excretion from 0.81 +/- 0.43% to 0.31 +/- 0.07% in hypertensive rats and from 1.05 +/- 0.37% to 0.47 +/- 0.18% in normotensive rats. High dose insulin infusion reduced (p less than 0.05) fractional sodium excretion from 0.67 +/- 0.22% to 0.21 +/- 0.08% in hypertensive rats and from 0.81 +/- 0.15% to 0.30 +/- 0.09% in normotensive rats. Sodium excretion was unchanged in time controls. The reduction in sodium excretion was similar in both rat groups during low dose and high dose insulin infusions. Mean arterial pressure and inulin clearance were unchanged from baseline values during insulin infusion in all rat groups. Glucose requirement to maintain euglycemia was greater (p less than 0.05) in normotensive than hypertensive rats at both insulin infusion rates. Thus, while hypertensive rats have reduced sensitivity to the hypoglycemic effects of insulin, the antinatriuretic response to insulin is not different from that of normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Passive enhancement of isolated pancreatic islet allografts.

Pancreatic islets from DA, Lewis, or DA X Lewis F1 rats were transplanted into the portal vein of Lewis or DA recipients made diabetic by prior treatment with Streptozotocin. The islets corrected the hyperglycaemia within 48 hr but were rejected within 5 days in all combinations. Passive enhancement of homozygous Lewis or DA islets with Lewis anti-DA or DA anti-Lewis antiserum in a single dose of 500 mul delayed rejection for several days, but where DA X Lewis F1 islets were used, rejection was delayed markedly with two of five animals in both the DA X Lewis F1 to DA and in DA microliters and 2.5 ml of enhancing serum were less effective than 500 mul in suppressing rejection. Thus, passive enhancement of allogeneic pancreatic islets was extremely effective in suppressing or delaying rejection of DA X Lewis F1 islets but was able to delay rejection of homozygous pancreatic islets by only a few days.

Functional connections of the rat medial cortex and basal forebrain: an in vivo intracellular study.

Projections between the medial cortex and basal forebrain in the rat were demonstrated by intracellular recordings and the anterograde tracer Phaseolus vulgaris leucoagglutinin. Direct projections between these areas were indicated by antidromic action potentials, short latency (less than 5 ms) orthodromic potentials, and labeled axon terminals in the basal forebrain subsequent to iontophoresis of Phaseolus vulgaris leucoagglutinin into posterior cingulate cortex. High proportions of antidromic action potentials were encountered in responsive cortical neurons (66%) and basal forebrain neurons (97%). Antidromic latencies recorded in the basal forebrain (less than 1.0 ms) revealed fast ascending projections; cortical neurons showed both fast and slow descending projections (latencies of 0.3-3.7 ms). Relatively few synaptic potentials (none in the diagonal band of Broca) and sparse labeling of axon terminals observed in the basal forebrain indicated that the ascending projections may be the more physiologically important or, at least, densest pathway. Polysynaptic feedforward pathways were suggested through long latency (greater than 20 ms) inhibitory and excitatory postsynaptic potentials, the former being the more common response. Candidate inhibitory neurons were identified in both cortex and basal forebrain. Possible monosynaptic (less than 5 ms) inhibitory postsynaptic and antidromic responses in these cells provided evidence that candidate inhibitory neurons participate in the reciprocal pathways.

The utility of a single sputum specimen in the diagnosis of tuberculosis. Comparison between HIV-infected and non-HIV-infected patients.

STUDY OBJECTIVES: (1) To assess the utility of a single sputum specimen in the evaluation of HIV-infected patients who are suspected of having tuberculosis (TB). (2) To identify radiographic findings that discriminate between HIV-infected patients with TB and those with pneumonia of other causes. DESIGN: Retrospective cohort analysis. PATIENTS: All patients evaluated at Harborview Medical Center, Seattle, between January 1986 and July 1994 in whom culture of respiratory secretions grew Mycobacterium tuberculosis or Mycobacterium avium-complex. Patients who were coinfected with HIV formed the primary study group. Their chest radiographs were then compared with those of a matched group of patients with pneumonia of other causes. MEASUREMENTS AND RESULTS: We identified 164 patients with TB, 20 of whom were HIV infected. The initial sputum specimen grew M tuberculosis in all HIV-infected patients and 99% of non-HIV-infected patients. Seventy percent of HIV-infected and 71% of non-HIV-infected patients had at least one positive smear. Most of these patients tested positive on their initial smear, and no significant difference was found between HIV-positive and HIV-negative patients (79% and 90%, respectively [p = 0.34]). The addition of a second sputum smear identified all HIV-infected patients and all but one in non-HIV-infected patients who were ultimately determined to be smear positive. A total of 27 HIV-infected patients had a positive acid-fast bacilli sputum smear during the study period, 14 of which were attributable to TB (specificity = 52%). The only radiographic findings that discriminated between HIV-infected patients with TB and those with pneumonia of other causes were the presence of cavitation or a miliary pattern (p = 0.014). CONCLUSIONS: A single sputum specimen was sufficient to establish the diagnosis in all HIV-infected patients with pulmonary TB. A single negative sputum smear made the diagnosis of TB significantly less likely. However, a minimum of two smears were necessary to achieve an acceptable early diagnostic yield. The presenting chest radiograph failed to discriminate between HIV-infected patients with TB and pneumonia of other causes in most cases.

Neurophysiological characterization of commissurally projecting dentate neurons in the rat.

Commissural neurons in the dentate hilus and in the deep dentate granule cell layer were recorded intracellularly in vivo, in conjunction with combined injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) at sites of electrical stimulation. Two hilar neurons responded with short latency antidromic spikes to stimulation of the contralateral dentate infrapyramidal molecular layer, but did not show any synaptic potentials, suggesting that these neurons do not receive commissural hilar input, either directly or indirectly, from the stimulating sites. On the other hand, 3 dentate-hilar border neurons responded to the contralateral hilar stimulation with antidromic spikes, excitatory postsynaptic potentials (EPSPs), orthodromic spikes, and inhibitory PSPs (IPSPs), suggesting a rich synaptic interaction both commissurally and locally in this region. No direct commissural inhibition was observed in any of the cells. PHA-L injection at the stimulation site indicated that commissural hilar axon terminals project to a limited region of the contralateral molecular layer in a lamellar fashion, and have only a sparse distribution in the contralateral hilus. The results indicate that rapidly conducting commissural neurons in the dentate gyrus are themselves inhibited in an indirect manner by commissural fibers.

Presynaptic enhancement of synaptic transmission in hippocampal cell cultures by phorbol esters.

The calcium-diacyglycerol activated protein kinase (C kinase) plays an important role in synaptic plasticity, and possibly in long-term potentiation (LTP). We have found that phorbol esters, which activate this protein kinase, increase the frequency of miniature excitatory postsynaptic currents (mEPCs) in hippocampal cell cultures. An analysis of distributions of these miniature synaptic currents shows that amplitudes, and thus postsynaptic function, are not influenced by phorbol esters. Synaptic transmission is therefore enhanced by phorbol esters at a presynaptic locus. The method of analysis employed here is applicable to a broad range of situations involving modification of synaptic transmission in the mammalian central nervous system.

Inhibition in subicular and entorhinal principal neurons in response to electrical stimulation of the fornix and hippocampus.

We performed experiments studying the responses of rat subicular and entorhinal neurons to electrical stimulation of the fornix and hippocampus. Four main results were obtained: (1) extracellular recordings from principal neurons showed prolonged inhibition in response to stimulation, and intracellular recordings showed prominent IPSPs; (2) neither fornical nor commissural afferents were necessary for the inhibitory responses; they were present even in animals that had received prior surgical sections of the fornix and hippocampal commissures; (3) antidromic responses to fornix or hippocampal stimulation were recorded in neurons of the subicular complex; and (4) 3 cells in the subicular and entorhinal cortex were encountered that showed some of the properties associated with interneurons. The results suggest that principal neurons of the subicular complex share a number of properties with hippocampal pyramidal cells, including intrinsic recurrent inhibitory circuitry. Further study is required to determine the pathway for entorhinal inhibitory responses.

Neurophysiology of the caudally directed hippocampal efferent system in the rat: projections to the subicular complex.

We studied the responses of rat subicular neurons to electrical stimulation of the hippocampus. Four main results were obtained: (1) orthodromic excitatory responses were recorded in neurons of the subicular complex following electrical stimulation of the ipsilateral hippocampus. Responses were usually characterized by a single action potential immediately followed by an inhibitory period. Intracellular recordings showed that spikes were triggered by EPSPs. Preliminary data indicated that the excitatory effects extend to the entorhinal cortex as well; (2) neither fornical nor commissural afferents were necessary for the responses; they were present even in animals that had received surgical sections of the fornix and hippocampal commissures prior to the neurophysiological experiments; (3) some neurons showed evidence of frequency potentiation when stimulated at 5/sec or 10/sec; and (4) neurons in hippocampal fields CA1 and CA3 with the physiological characteristics of pyramids could be antidromically activated by electrical stimulation of subicular white matter. The results indicate an excitatory, caudally directed hippocampal efferent system that originates in fields CA1 and CA3, and that projects to all ventrocaudal regions of the subicular complex.

Demonstration of caudally directed hippocampal efferents in the rat by intracellular injection of horseradish peroxidase.

Axonal projections of rat hippocampal neurons were demonstrated by intracellular injections of horseradish peroxidase. The data indicated a prominent caudally directed projection from pyramidal neurons of hippocampal field CA1, provided evidence that the subiculum is one of its targets, and suggested that the caudally directed efferents from CA1 are more numerous than rostrally directed ones.

Commissural responses of rat retrohippocampal neurons.

Synaptic responses of commissurally activated rat subicular and entorhinal neurons were studied intracellularly in vivo by stimulating the contralateral dentate gyrus. The most prominent synaptic responses in both subicular and entorhinal neurons were inhibitory postsynaptic potentials (IPSPs). IPSPs were generated in combination with antidromic spikes and/or excitatory postsynaptic potentials (EPSPs) and orthodromic spikes. No dependency between any two response types were found. Commissurally projecting subicular neurons (identified by the presence of antidromic spikes evoked by contralateral stimulation) were found, extending previous anatomical studies. Commissurally projecting entorhinal neurons were found in layer II, confirming previous anatomical studies. Positive correlations between antidromic spike latency and depth of recording sites supported the interpretation that axons projected along the fiber bundles of the hippocampal commissures and angular bundle to distribute to their targets. Possible circuits that could have mediated the excitatory and inhibitory responses of these retrohippocampal neurons are considered.

Physiological evidence for an excitatory pathway from entorhinal cortex to amygdala in the rat.

We studied the responses of amygdala neurons to entorhinal cortex stimulation in anaesthetized rats. Intracellular and extracellular data were obtained in a total of 16 cells located throughout the amygdaloid complex and two cells in adjacent piriform cortex. In addition, antidromic responses to amygdala stimulation were obtained in 7 cells of the entorhinal or perirhinal cortex. All recordings in the amygdala showed orthodromic excitatory responses (spikes or EPSPs), with a mean latency of 8 ms. These were succeeded by IPSPs with a mean latency of 15 ms. Two cells in piriform cortex responded to entorhinal stimulation with inhibition alone. A cell in the region of the basomedial nucleus showed characteristics of an inhibitory interneuron. Cells in entorhinal and perirhinal cortex responding antidromically to amygdala stimulation were found primarily in layers III-V. Axons of one such cell, which was injected with HRP, were seen to course rostrally to the region of the amygdala within the fiber tract of the external capsule. Three entorhinal cells (layer III) responded antidromically to both amygdala and hippocampal formation stimulation. A neuronal circuit diagram accounting for our findings is presented.

Demonstration of axonal projections of neurons in the rat hippocampus and subiculum by intracellular injection of HRP.

Hippocampal formation neurons of rat were injected intracellularly with horseradish peroxidase in order to trace intrinsic and extrinsic axonal projections. CA3 pyramids (n = 9) projected axons rostrally toward the fimbria, one or more Schafer collaterals toward CA1, and in two cases fibers that crossed the hippocampal commissure. Pyramids of CA1 (n = 5) projected axons to the alveus where they proceeded caudally toward the subiculum. A subset (n = 3) also projected an axonal branch rostrally toward the fimbria. These findings confirm not only major target regions of Ammon's horn pyramids, but also emphasize their divergent axonal projections that are not necessarily lamellar in organization. Axons from subicular pyramids (n = 12) projected rostrally, caudally, or in both directions. They could be traced to several other cortical regions, specifically Ammon's horn, entorhinal cortex and cingulate cortex. The results further confirm that subicular neurons are the recipient of input from the hippocampus proper and are a principal source of efferents from the hippocampal formation. A multi-process neuron in CA1 with physiologic properties associated with inhibitory interneurons was filled and traced in detail. It most resembled the poligonal basket cells that Lorente de Nó described, having long radially oriented dendrites extending as far as stratum lacunosum-moleculare. The presence of putative inhibitory interneuron dendrites in stratum lacunosum-moleculare suggests some role other than traditional recurrent inhibition for these dendritic segments, and two possible circuits are described.

Convergence of projections from the rat hippocampal formation, medial geniculate and basal forebrain onto single amygdaloid neurons: an in vivo extra- and intracellular electrophysiological study.

We recorded extra- and intracellular responses from rat amygdaloid neurons in vivo after electrical stimulation of the hippocampal formation (dentate gyrus, hippocampal fields CA3 and CA4, entorhinal cortex, subicular complex); medial geniculate; and basal forebrain (diagonal band, ventral pallidum, olfactory tubercle, nucleus accumbens, bed nucleus of stria terminalis, lateral preoptic area, substantia innominata). Stimulation of hippocampal formation structures evoked IPSPs or EPSP-IPSP sequences in which the IPSP had a lower threshold than the EPSP. Recordings from candidate inhibitory neurons in the amygdala indicated that excitatory afferents from the hippocampal formation contact both amygdaloid inhibitory and principal neurons (feedforward inhibition), and that the inhibitory neurons have a lower threshold of activation. Medial geniculate stimulation also evoked EPSP-IPSP sequences. In marked contrast to these results, stimulation of basal forebrain structures evoked short latency IPSPs in amygdaloid neurons. This provides the first physiological evidence for direct inhibition of the amygdala by the basal forebrain. Basal forebrain stimulation also evoked EPSP-IPSP sequences in amygdaloid neurons. Individual amygdaloid neurons could show responses to stimulation of the hippocampal formation, basal forebrain, and medial geniculate, indicating that synaptic input from these areas converges onto single amygdaloid cells. The findings provide further information about the synaptic organization of afferents to the amygdala, and indicate that single amygdaloid neurons play a role in the synaptic integration of input from these diverse sources.

Neurophysiology and neuropharmacology of projections from entorhinal cortex to striatum in the rat.

We studied projections from the entorhinal cortex (Ent) to the striatum in anesthetized rats using extra- and intracellular recording and multibarrel iontophoresis. The majority of recording were from the caudate-putamen (CPu) and core of the nucleus accumbens (AcbC). Electrical stimulation of the Ent evoked synaptic responses in 77% of tests with AcbC neurons and 48% of tests with CPu neurons. In the case of AcbC neurons, 61% of these tests proved to be excitatory and were often followed by inhibitory phases. In contrast to this, only 18% of tests from CPu neurons were excitatory. Intracellular HRP labeling showed that responsive cells were medium spiny neurons. During iontophoretic experiments, application of the glutamatergic AMPA antagonist DNQX could selectively decrease or block excitatory responses. The GABAA antagonist bicuculline methiodide increased cellular firing rates and could reveal excitatory responses, suggesting block of a short-latency, short-duration inhibitory component. Ejection of the GABAB antagonist CGP-35348 could attenuate a later, longer-duration component of inhibition. The results indicate that the Ent excites striatal neurons at least in part by glutamatergic receptors and suggest that this excitation is followed by secondary prolonged GABAergic inhibition.