Networks of VTA Neurons Encode Real-Time Information about Uncertain Numbers of Actions Executed to Earn a Reward.

Multiple and unpredictable numbers of actions are often required to achieve a goal. In order to organize behavior and allocate effort so that optimal behavioral policies can be selected, it is necessary to continually monitor ongoing actions. Real-time processing of information related to actions and outcomes is typically assigned to the prefrontal cortex and basal ganglia, but also depends on midbrain regions, especially the ventral tegmental area (VTA). We were interested in how individual VTA neurons, as well as networks within the VTA, encode salient events when an unpredictable number of serial actions are required to obtain a reward. We recorded from ensembles of putative dopamine and non-dopamine neurons in the VTA as animals performed multiple cued trials in a recording session where, in each trial, serial actions were randomly rewarded. While averaging population activity did not reveal a response pattern, we observed that different neurons were selectively tuned to low, medium, or high numbered actions in a trial. This preferential tuning of putative dopamine and non-dopamine VTA neurons to different subsets of actions in a trial allowed information about binned action number to be decoded from the ensemble activity. At the network level, tuning curve similarity was positively associated with action-evoked noise correlations, suggesting that action number selectivity reflects functional connectivity within these networks. Analysis of phasic responses to cue and reward revealed that the requirement to execute multiple and uncertain numbers of actions weakens both cue-evoked responses and cue-reward response correlation. The functional connectivity and ensemble coding scheme that we observe here may allow VTA neurons to cooperatively provide a real-time account of ongoing behavior. These computations may be critical to cognitive and motivational functions that have long been associated with VTA dopamine neurons.

Change-point detection of cognitive states across multiple trials in functional neuroimaging.

Many functional neuroimaging-based studies involve repetitions of a task that may require several phases, or states, of mental activity. An appealing idea is to use relevant brain regions to identify the states. We developed a novel change-point methodology that adapts to the repeated trial structure of such experiments by assuming the number of states stays fixed across similar trials while allowing the timing of change-points to change across trials. Model fitting is based on reversible-jump MCMC. Simulation studies verified its ability to identify change-points successfully. We applied this technique to data collected via functional magnetic resonance imaging (fMRI) while each of 20 subjects solved unfamiliar arithmetic problems. Our methodology supplies both a summary of state dimensionality and uncertainty assessments about number of states and the timing of state transitions. Copyright © 2016 John Wiley & Sons, Ltd.

Development and validation of a model predictive of occult nipple involvement in women undergoing mastectomy.

BACKGROUND: This prospective study aimed to build a predictive model using preoperative information to aid selection for nipple-sparing mastectomy. METHODS: Two hundred consecutive skin-sparing mastectomy specimens without overt nipple involvement were evaluated. Demographic, preoperative pathology and imaging information was collected. Nipple specimens (2 x 2 x 2 cm) were sectioned at 3-mm intervals. Haematoxylin and eosin-stained slides were examined by a breast pathologist for involvement by tumour. Logistic regression analyses of 65 therapeutic procedures identified factors associated with occult involvement and created a predictive model. This was tested on specimens from a further 65 therapeutic procedures. RESULTS: Occult nipple involvement was noted in 32 (24.6 per cent) of 130 mastectomy specimens. In the training set, imaging diameter of the lesion and its distance from the nipple predicted nipple involvement on univariable analysis (P = 0.011 and P = 0.014 respectively). The multivariable logistic regression model was validated in the test set. The areas under the receiver-operating characteristic curve were 0.824 and 0.709 for the training and test sets respectively. CONCLUSION: Three-quarters of women undergoing mastectomy did not have occult nipple involvement. A clinical tool including tumour size and distance from the nipple has been developed to improve patient selection for nipple-sparing mastectomy.

Recovery of visual field and acuity after removal of epiretinal and inner limiting membranes.

BACKGROUND: Visual acuity serves as only a rough gauge of macular function. The aim therefore was to ascertain whether central an assessment of the central visual field afforded a closer insight into visual function after removal of epiretinal membranes and Infracyanine-Green- or Trypan-Blue-assisted peeling of the inner limiting membrane. PATIENTS AND METHODS: Fourty-three patients undergoing pars-plana vitrectomy for the removal of epimacular membranes and dye-assisted peeling of the inner limiting membrane using either Infracyanine Green (n = 29; group 1) or Trypan Blue (n = 14; group 2) were monitored prospectively for 12 months. Preoperatively, and 1, 6 and 12 months postoperatively, distance and reading visual acuities were evaluated; the central visual field was assessed by automated static perimetry. RESULTS: Twelve months after surgery, distance and reading visual acuities had improved in both groups, but to a significant degree only in Trypan-Blue-treated eyes. The difference between the two groups was not significant. Likewise at this juncture, the mean size of the visual-field defect remained unchanged in Trypan-Blue-treated eyes (preoperative: 4.3 (SD 2.1) dB; 12 months: 4.0 (2.1) dB (p = 0.15)), but had increased in Infracyanine-Green-treated ones (from 5.3 (3.7) dB to 8.0 (5.2) dB (p = 0.027)). CONCLUSION: Unlike visual acuity, the central visual field had deteriorated in Infracyanine-Green-treated eyes but not in Trypan-Blue-treated eyes 12 months after surgery. Hence, as a predictor of functional outcome, testing of the central visual field may be a more sensitive gauge than visual acuity. Furthermore, Infracyanine Green may have a chronic and potentially clinically relevant effect on the macula which is not reflected in the visual acuity.

PVR recurrence and the timing of silicon oil removal.

BACKGROUND: Following vitrectomy for PVR-associated retinal detachment, placement of an encircling band, filling with silicone oil (SO) and successful retinal reattachment, a recurrence of PVR can develop. Retinal redetachment after SO removal is usually due to secondary or residual PVR. We wanted to ascertain whether the anatomical and functional outcomes of surgery in patients with a reattached retina and recurrent PVR can be improved by delaying the removal of SO. PATIENTS AND METHODS: 112 consecutive patients with PVR-associated retinal detachment who had undergone vitrectomy with SO filling, were monitored for at least 6 months after SO removal. Prior to SO removal, the retina posterior to the encircling band had to be completely reattached. Patients who developed PVR after SO filling were divided into two groups according to the duration of SO retention: 12 - 18 months (group 2: n = 48); > 18 months (group 3: n = 21). Individuals without PVR recurrence after SO filling and in whom the SO was consequently removed within 4 - 12 months served as control (group 1: n = 43). Anatomical success, intraocular pressure (IOP) and best-corrected visual acuity (BCVA) served as the primary clinical outcome parameters. RESULTS: Six months after SO removal, the anatomical success rates (86.3 %, 88.8 % and 84.6 %, in groups 1, 2 and 3, respectively; log rank = 0.794) and the BCVAs (p = 0.861) were comparable in the three groups. Mean IOP (p = 0.766), and the frequency of complications such as PVR recurrence (p = 0.936), bullous keratopathy (p = 0.981) and macular pucker (p = 0.943) were likewise similar. Patients in whom SO was retained for more than 18 months had the highest IOPs and required the heaviest dosage with anti-glaucoma drugs. CONCLUSIONS: In patients who develop a recurrence of PVR after vitrectomy and SO filling the surgeon can observe and treat retinal changes for up to 18 months without impairing the anatomical and functional outcomes. The retention of SO for more than 18 months does not improve the anatomical outcome. However, it can impair the functional outcome by precipitating the development of a persisting secondary glaucoma.

Vitrectomy for juvenile uveitis: prognostic factors for the long-term functional outcome.

PURPOSE: This study evaluated the long-term effect of pars plana vitrectomy (PPV) in children and adolescents with chronic uveitis on visual function, anatomical outcome, and the requirement of systemic treatment. Further, predictive preoperative factors associated with a beneficial visual outcome were assessed. METHODS: Retrospective review of 29 eyes of 23 consecutive paediatric and juvenile patients below 20 years of age with chronic uveitis who underwent a PPV for visually significant opacities in 25 eyes, vitreous haemorrhage in three eyes, and retinal detachment in one eye. The clinical diagnosis was chronic intermediate uveitis in 22 eyes and retinal vasculitis of different origin in seven eyes. RESULTS: LogMAR visual acuity improved from an average of 0.91 to 0.33 (P<0.001). Cystoid macular oedema (CME) was significantly reduced in eight of 10 eyes postoperatively (P=0.021). In the multiple regression analysis, a low preoperative logMAR visual acuity and the presence of a CME had a negative influence on the final logMAR visual acuity. Furthermore, the appearance of chronic uveitis relapses was significantly reduced from 15 eyes before to seven eyes after surgery (P=0.042). CONCLUSIONS: PPV has a beneficial effect on the course and the complications of chronic uveitis in paediatric and juvenile patients with respect to the anatomical and visual outcome. Preoperative logMAR visual acuity and clinically significant CME were the most accurate predictors for the functional outcome.

[Pars plana vitrectomy for idiopathic vitreous floaters]. / Pars-plana-Vitrektomie bei idiopathischen Glaskörpertrübungen.

BACKGROUND: The aim of this study was to evaluate the role of pars plana vitrectomy (PPV) in patients with persistent vitreous floaters (VF) in phakic (56.7 %) or pseudophakic (43.3 %) eyes. SUBJECTS AND METHODS: A retrospective study of 24 consecutive patients (30 eyes) who underwent a 2-port-PPV using indirect opthalmoscopy between 1992 and 2003 was carried out. Main outcome measures were postoperative visual acuity (PVA), incidence of postoperative complications and patient satisfaction, which has been assessed retrospectively using a detailed questionnaire. RESULTS: Symptoms resolved in all patients. PVA was significantly better (0.91 +/- 0.2 vs. 0.84 +/- 0.2 preoperative visual acuity) or equal in 25 patients (83.3 %). One pseudophakic patient (3.3 %) experienced a retinal detachment 48 months after surgery. In 5 of 17 phakic eyes (35 %) a cataract extraction had to be performed during the follow-up period. All patients were satisfied with their overall visual function. DISCUSSION: This study shows PPV to be a safe and effective primary treatment for visually disturbing VF. In spite of the small number of cases with a lower PVA (5 eyes/16.7 %), which in the most severe case corresponded to a reduction of VA from 1.0 to 0.6 due to a nuclear sclerosis of the lens, all patients were satisfied. As vitreoretinal complications may occur, a critical patient selection and a careful preoperative assessment of specific risks of vitrectomy are mandatory.

Comparison of intra-arterial thrombolysis with conventional treatment in patients with acute central retinal artery occlusion.

BACKGROUND: Several case series and a recent meta-analysis indicate that intra-arterial thrombolysis (IAT) is effective for the treatment of acute central retinal artery occlusion (CRAO). METHODS: A total of 37 patients with acute monocular blindness because of unilateral thromboembolic CRAO were treated with IAT using urokinase within six hours of the onset of symptoms. Visual outcome was compared with a control group of 19 patients, also seen within six hours, who did not undergo thrombolytic treatment. In both groups some patients were treated by paracentesis and/or acetazolamide. Predictors of visual outcome were evaluated. RESULTS: Visual improvement was more likely with IAT (p = 0.01) as were the chances to regain visual acuity of >0.6 significantly better (p = 0.04): 8/37 patients (22%) regained visual acuity of >0.6 in the IAT group and none (0/19) in the control group. Younger patients were more likely to regain some vision with (p = 0.012) or without IAT (p = 0.026). Three patients had minor treatment related cerebral ischaemic events, two had transient ischaemic attacks and one a minor stroke. There were no haemorrhagic complications. CONCLUSIONS: This series of patients with CRAO demonstrated that IAT enhanced the chances of visual improvement compared with conventional treatment only. Furthermore, younger patients have a better chance to achieve some visual recovery.

Primary retinal reattachment surgery: anatomical and functional outcome in phakic and pseudophakic eyes.

AIM: To compare the anatomical and functional success of primary scleral buckling, performed either alone or in combination with vitrectomy, for primary retinal detachment (RD) in phakic eyes and in eyes had undergone uneventful phacoemulsification and had received posterior chamber lens implantations. METHODS: A total of 243 consecutive patients were included in this retrospective, nonrandomized comparative study. In all, 165 phakic and 78 pseudophakic individuals with primary RD underwent scleral buckling alone or in combination with vitrectomy and were followed up for 6 months. Pre-, intra- and postoperative findings including anatomical success, best-corrected visual acuity (BCVA), complications, and the development of proliferative vitreoretinopathy (PVR), macular pucker, or secondary cataracts were recorded. Cases requiring more than one surgical intervention were defined having failed, although further surgical intervention might have led to success. RESULTS: At 6 months after scleral buckling alone, the anatomical success was similar in phakic (88.98%) and pseudophakic (87.65%) eyes (log rank=0.310). The corresponding results after scleral buckling with vitrectomy were 82.13 and 77.63% for phakic and pseudophakic eyes, respectively (log rank=0.799). At 6 months after scleral buckling alone, BCVA was similar in phakic and pseudophakic eyes (0.62+/-0.30 vs 0.70+/-0.29; P=0.227). Likewise, after scleral buckling with vitrectomy, BCVA did not differ significantly (P=0.322) between phakic (0.34+/-0.32) and pseudophakic eyes (0.50+/-0.27). CONCLUSION: The anatomical and functional outcome of primary retinal reattachment surgery, involving scleral buckling alone or in combination with vitrectomy, is similar in phakic and pseudophakic eyes.

Morphological observations regarding the origins of atypical cystic lobules (low-grade clinging carcinoma of flat type).

This study seeks to define the morphological pathogenesis of a form of cystic transformation of lobules referred to as atypical cystic lobule or low-grade clinging carcinoma of flat type. We collected 25 examples that seem to represent the early stages in the formation of atypical cystic lobules and made a careful study of their morphology. Our observations indicate that this lesion arises from pre-existing, structurally normal terminal duct-lobular units and that it seems to develop by the direct transformation of indigenous luminal cells. The transformed cells first become evident in the small duct or terminal ductule, where they appear as slightly enlarged columnar cells containing atypical nuclei. In more advanced examples, these alterations affect all luminal cells of the terminal duct-lobular unit, but the cells of the terminal ductule continue to show more pronounced changes than the cells lining the acini. The atypical cells within the lobule do not seem to displace the normal acinar cells. Instead, the cells form a continuum, making it impossible to define the point at which atypical cells and normal cells meet. Within the small duct, however, the atypical epithelium comes to an abrupt halt as the duct courses towards the nipple. Considering these observations, we ascribe the formation of atypical cystic lobules to the accumulation of atypical cells in pre-existing terminal duct-lobular units.

Atypical cystic lobules in patients with lobular neoplasia.

We analyzed the frequency and anatomic distribution of atypical cystic lobules (ACLs) in patients whose index biopsy specimen contained lobular neoplasia (LN). Thirty of 54 patients (56%) had ACLs in their index biopsy specimen. Five of the patients whose index biopsy lacked ACLs underwent an additional biopsy, and 4 of these patients had ACLs in an additional specimen, bringing the total number of patients having both ACLs and LN to 34 of 54 (62.9%). ACLs involved both breasts with equal frequency and neither the extent of the involvement nor the anatomic location of the LN paralleled the distribution of the ACLs. The presence of ACLs in patients with LN might explain its increased risk for the development of ductal carcinomas and their bilateral distribution. Int J Surg Pathol 9(3):201-206, 2001

Ovarian hormone receptors in human mammary stromal cells.

Mesenchymal cells of the rodent breast express both estrogen and progesterone receptors. Searches for these molecules in the human breast have yielded conflicting results. Following immunohistochemical staining of samples of normal human breast tissue, the authors detected estrogen receptor alpha protein and progesterone receptor protein in extralobular (non-specialized) fibroblasts and estrogen receptor alpha protein in adipocytes. Tissues from young teenage girls and pregnant women contained the greatest number of receptor positive fibroblasts. These observations confirm prior reports of the presence of ovarian hormone receptors in mammary fibroblasts. The findings also illustrate similarities in the organization of the rodent and human breasts and thereby suggest that regulation of the gland by ovarian hormones involves similar mechanisms in both species.

Lobular carcinoma in situ and infiltrating ductal carcinoma: frequent presence of DCIS as a precursor lesion.

Infiltrating ductal carcinoma (IDC) occurs frequently in patients with lobular carcinoma in-situ (LCIS). LCIS is not thought to be the direct precursor of the invasive component. The authors analyzed 15 cases of coexisting LCIS and IDC and found ductal carcinoma in situ (DCIS) in 12. The DCIS and IDC were of similar grade and located in the same area. Selected cases stained with E-cadherin demonstrated a different immunophenotype for the lobular and ductal lesions. These results support the notion that DCIS is the direct precursor of IDC occurring in patients with LCIS.

Solid low-grade in situ carcinoma of the breast: role of associated lesions and E-cadherin in differential diagnosis.

Low-grade solid in situ carcinomas of the breast are difficult to classify. The authors investigated 12 cases of in situ carcinomas with equivocal features and correlated their histologic attributes with those of the associated invasive carcinomas as well as with E-cadherin expression in both in situ and invasive disease. E-cadherin-positive in situ lesions were invariably associated with invasive carcinomas of the ductal type. In situ carcinomas that were E-cadherin negative were associated with invasive carcinomas of the lobular type in five of six cases. In all cases, the invasive carcinomas showed the same pattern of E-cadherin reactivity as the in situ lesions. Sharply defined cellular membranes, necrosis, and occasional microacini were seen in both E-cadherin-positive and negative in situ carcinomas, whereas intracytoplasmic lumina and a noncohesive appearance were seen only in E-cadherin-negative lesions.

Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells.

A number of genetic mutations have been identified in human breast cancers, yet the specific combinations of mutations required in concert to form breast carcinoma cells remain unknown. One approach to identifying the genetic and biochemical alterations required for this process involves the transformation of primary human mammary epithelial cells (HMECs) to carcinoma cells through the introduction of specific genes. Here we show that introduction of three genes encoding the SV40 large-T antigen, the telomerase catalytic subunit, and an H-Ras oncoprotein into primary HMECs results in cells that form tumors when transplanted subcutaneously or into the mammary glands of immunocompromised mice. The tumorigenicity of these transformed cells was dependent on the level of ras oncogene expression. Interestingly, transformation of HMECs but not two other human cell types was associated with amplifications of the c-myc oncogene, which occurred during the in vitro growth of the cells. Tumors derived from the transformed HMECs were poorly differentiated carcinomas that infiltrated through adjacent tissue. When these cells were injected subcutaneously, tumors formed in only half of the injections and with an average latency of 7.5 weeks. Mixing the epithelial tumor cells with Matrigel or primary human mammary fibroblasts substantially increased the efficiency of tumor formation and decreased the latency of tumor formation, demonstrating a significant influence of the stromal microenvironment on tumorigenicity. Thus, these observations establish an experimental system for elucidating both the genetic and cell biological requirements for the development of breast cancer.

Mammographic appearance of ductal carcinoma in situ does not reliably predict histologic subtype.

Histologic subtypes of ductal carcinoma in situ (DCIS) have been correlated with disease prognosis. There are conflicting reports on whether the grade of DCIS can be predicted by the morphology of calcifications seen on mammography. We undertook this study to determine whether the grade of DCIS can be reliably and accurately determined by mammography prior to excisional biopsy. Ninety consecutive cases of DCIS from 1993 to 1996 were identified, of which 75 cases had mammograms available for review. Any lesion with invasion was excluded. The mammogram showed only a mass in 10 of 75 cases, a mass and calcifications in 3 of 75 cases, and calcifications alone in 62 of 75 cases. Three board-certified radiologists with special expertise in mammography reviewed and categorized the mammographic findings as well, intermediate or poorly differentiated DCIS without knowledge of the histologic diagnosis. Histologic grading was performed without knowledge of the mammographic finding. Receiver operating curves (ROCs) were computed for each of the radiologists. For microcalcifications, the ROC comparisons of the radiologists' opinions of tumor grade and random chance were not significantly different. In those cases with available magnification views, the grade assessment did not change significantly. If only a mass was present on mammography, well-differentiated DCIS was the predominant histologic subtype. A histologic grade of DCIS cannot accurately be determined prospectively based on the mammographic appearance of microcalcifications. However, if only a mass is present, this is more likely to represent well-differentiated DCIS.

Influence of refractive correction on peripheral visual field in static perimetry.

PURPOSE: To determine the influence of refractive errors on peripheral visual field thresholds in automated static perimetry. METHODS: In 47 subjects (age 16-49 years), the difference of perimetric thresholds was tested in the peripheral visual field without and with contact lens correction, using a custom-made program (Goldmann stimulus size III) with the automated perimeter Octopus 2000 R. Refractive errors ranged from -16.75 to +12.5 diopters. Sixty-four test locations on three concentric rings between 30 degrees and 50 degrees in 19 hyperopic and 28 myopic eyes were tested. RESULTS: All rings in myopic eyes revealed a significant influence of refraction on the differential light sensitivity in the peripheral visual field. In hyperopic eyes only the inner ring showed a significant influence of refraction. The decrease in sensitivity, measured in dB/diopter, for the myopic inner ring was 0.75; for the myopic middle ring it was 0.46; for the myopic outer ring it was 0.22; and for the hyperopic inner ring it was 0.40. CONCLUSIONS: A significant association between refractive errors and differential light sensitivity exists in the peripheral visual field of myopic eyes. Therefore, contact lens wear is recommended when performing automated perimetry of the peripheral visual field of myopic patients with higher refractive errors.

Atypical cystic lobule of the breast: an early stage of low-grade ductal carcinoma in-situ.

The authors describe the characteristics of atypical cystic lobules (ACLs), which represent a step in the formation of low-grade ductal carcinoma in-situ. The authors define ACLs as a proliferation of luminal cells showing low-grade cytological atypia without architectural atypia. ACLs were compared with conventional hyperplasia, low-grade ductal carcinoma in-situ, and lobular neoplasia. 1) In about 40% of the cases, atypical cystic lobules merged with fully established micropapillary/cribriform ductal carcinoma in-situ. 2) Immunohistochemical staining for hormone receptors, keratin nineteen, and cyclin D1 revealed that atypical cystic lobules demonstrate a consistent immunophenotype, which differs from that of normal lobules and benign lesions and matches the one of low-grade ductal carcinoma in-situ. 3) ACLs are sometimes calcified. Osteopontin-positive histiocytes infiltrated all Kossa-positive (type II microcalcification) cribriform and comedo-type carcinomas and ACLs. The similarities in cytological and immunohistochemical features, the close proximity of the two types of proliferation, and the similarities with respect to calcification suggest that atypical cystic lobules represent an early stage in the formation of certain types of low-grade ductal carcinoma in-situ.

Atypical cystic lobules: an early stage in the formation of low-grade ductal carcinoma in situ.

Evidence from many studies has established the neoplastic potential of ductal carcinoma in situ, but the origin and the morphological characteristics of the early stages of this proliferation remain unidentified. Workers writing in the early twentieth century observed a cystic transformation of lobules and proposed that it represented one such early stage, and contemporary European and Japanese pathologists have reached the same conclusion. We describe the characteristics of this cystic transformation, which we call us "atypical cystic lobules," and present evidence to support the proposal that the alteration is a step in the formation of low-grade ductal carcinoma in situ. Atypical cystic lobules are a proliferation of luminal cells showing low-grade cytological atypia without architectural atypia. The study group comprised 21 cases of atypical cystic lobules from specimens also showing conventional low-grade ductal carcinoma in situ or lobular neoplasia. Immunohistochemical staining for hormone receptors, keratin 19, and cyclin D1 revealed that atypical cystic lobules demonstrated a consistent immunophenotype, which differs from the pattern shown by normal lobules and benign lesions and matches that of low-grade ductal carcinoma in situ. In about 40% of the cases, atypical cystic lobules merged with fully established micropapillary/cribriform ductal carcinoma in situ. The similarities in the cytological and immunohistochemical features and the proximity of the two types of proliferation suggest that atypical cystic lobules represent an early stage in the formation of certain types of low-grade ductal carcinoma in situ.