Brain Charts for the Rhesus Macaque Lifespan.

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03).

BACKGROUND: The combinations of methotrexate, vinblastine, Adriamycin, cisplatin (Pharmanell, Athens, Greece) (MVAC) or gemcitabine, cisplatin (GC) represent the standard treatment of advanced urothelial cancer (UC). Dose-dense (DD)-MVAC has achieved longer progression-free survival (PFS) than the conventional MVAC. However, the role of GC intensification has not been studied. We conducted a randomized, phase III study comparing a DD-GC regimen with DD-MVAC in advanced UC. PATIENTS AND METHODS: One hundred and thirty patients were randomly assigned between DD-MVAC: 66 (M 30 mg/m(2), V 3 mg/m(2), A 30 mg/m(2), C 70 mg/m(2) q 2 weeks) and DD-GC 64 (G 2500 mg/m(2), C 70 mg/m(2) q 2 weeks). The median follow-up was 52.1 months (89 events). RESULTS: The median overall survival (OS) and PFS were 19 and 8.5 months for DD-MVAC and 18 and 7.8 months for DD-GC (P = 0.98 and 0.36, respectively). Neutropenic infections were less frequent for DD-GC than for DD-MVAC (0% versus 8%). More patients on DD-GC received at least six cycles of treatment (85% versus 63%, P = 0.011) and the discontinuation rate was lower for DD-GC (3% versus 13%). CONCLUSIONS: Although DD-GC was not superior to DD-MVAC, it was better tolerated. DD-GC could be considered as a reasonable therapeutic option for further study in this patient population. Clinical Trial Number ACTRN12610000845033, www.anzctr.org.au.

Deep Learning Segmentation of the Nucleus Basalis of Meynert on 3T MRI.

BACKGROUND AND PURPOSE: The nucleus basalis of Meynert is a key subcortical structure that is important in arousal and cognition and has been explored as a deep brain stimulation target but is difficult to study due to its small size, variability among patients, and lack of contrast on 3T MR imaging. Thus, our goal was to establish and evaluate a deep learning network for automatic, accurate, and patient-specific segmentations with 3T MR imaging. MATERIALS AND METHODS: Patient-specific segmentations can be produced manually; however, the nucleus basalis of Meynert is difficult to accurately segment on 3T MR imaging, with 7T being preferred. Thus, paired 3T and 7T MR imaging data sets of 21 healthy subjects were obtained. A test data set of 6 subjects was completely withheld. The nucleus was expertly segmented on 7T, providing accurate labels for the paired 3T MR imaging. An external data set of 14 patients with temporal lobe epilepsy was used to test the model on brains with neurologic disorders. A 3D-Unet convolutional neural network was constructed, and a 5-fold cross-validation was performed. RESULTS: The novel segmentation model demonstrated significantly improved Dice coefficients over the standard probabilistic atlas for both healthy subjects (mean, 0.68 [SD, 0.10] versus 0.45 [SD, 0.11], P = .002, t test) and patients (0.64 [SD, 0.10] versus 0.37 [SD, 0.22], P < .001). Additionally, the model demonstrated significantly decreased centroid distance in patients (1.18 [SD, 0.43] mm, 3.09 [SD, 2.56] mm, P = .007). CONCLUSIONS: We developed the first model, to our knowledge, for automatic and accurate patient-specific segmentation of the nucleus basalis of Meynert. This model may enable further study into the nucleus, impacting new treatments such as deep brain stimulation.

The sensory nature of mnemonic representation in the primate prefrontal cortex.

A long-standing issue concerning the function of the primate dorsolateral prefrontal cortex is whether the activity of prefrontal neurons reflects the perceived sensory attributes of a remembered stimulus, or the decision to execute a motor response. To distinguish between these possibilities, we recorded neuronal activity from monkeys trained to make a saccade toward the brighter of two memoranda, under conditions of varied luminance. Our results indicated that during the delay period when sensory information was no longer available, neuronal discharge was modulated by the luminance of the stimulus appearing in the receptive field, and was directly correlated with psychophysical performance in the task. The findings suggest that although prefrontal cortex codes for a diversity of representations, including the decision for an impending response, a population of neurons maintains the dimensional attributes of remembered stimuli throughout the delay period, which allows for flexibility in the outcome of a mnemonic process.

Coding specificity in cortical microcircuits: a multiple-electrode analysis of primate prefrontal cortex.

Neurons with directional specificities are active in the prefrontal cortex (PFC) during tasks that require spatial working memory. Although the coordination of neuronal activity in PFC is thought to be maintained by a network of recurrent connections, direct physiological evidence regarding such networks is sparse. To gain insight into the functional organization of the working memory system in vivo, we recorded simultaneously from multiple neurons spaced 0.2-1 mm apart in monkeys performing an oculomotor delayed response task. We used cross-correlation analysis and characterized the effective connectivity between neurons in relation to their spatial and temporal response properties. The majority of narrow (<5 msec) cross-correlation peaks indicated common input and were most often observed between pairs of neurons within 0.3 mm of each other. Neurons recorded at these distances represented the full range of spatial locations, suggesting that the entire visual hemifield is represented in modules of corresponding dimensions. Nearby neurons could be activated in any epoch of the behavioral task (stimulus presentation, delay, response). The incidence and strength of cross-correlation, however, was highest among cells sharing similar spatial tuning and similar temporal profiles of activation across task epochs. The dependence of correlated discharge on the functional properties of neurons was observed both when we analyzed firing from the task period as well as from baseline fixation. Our results suggest that the coding specificity of individual neurons extends to the local circuits of which they are part.

The contribution of cavernous body biopsy in the diagnosis and treatment of male impotence.

This study concerns the results of penile biopsies in 50 patients aged 27 to 80, with secondary impotence removed with a biopty gun or during penile surgery. The biopty gun specimens were equally representative as the open biopsy ones. The cause and the degree of erectile dysfunction were determined by clinical and laboratorial investigation. The histological study of the cavernous bodies in the patients with psychogenic impotence revealed normal erectile tissue. In patients with organic impotence, histological lesions were graded as mild, moderate or severe. The most severe lesions were observed in the erectile tissue and in particular in the smooth muscle of the trabeculae and the helicine arteries, which had been reduced and replaced by connective tissue. Histological lesions were found not only in the arterial but also in the venous leak cases. There was a correlation between their severity and the degree of impotence, although of no statistical significance. The penile biopsy determines the condition (state) of the functional cavernous smooth muscle tissue, the integrity of which is essential for the erectile mechanism as well as for the action of the vasoactive drugs and the results of vascular surgery. Its important role is evident as it contributes not only to the diagnosis of the cause, but also to the choice of treatment of male impotence.

Oral estramustine and oral etoposide for hormone-refractory prostate cancer.

OBJECTIVES: Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC). METHODS: Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression. RESULTS: Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival. CONCLUSIONS: We conclude that the combination of estramustine and etoposide is an active and well-tolerated oral regimen in HRPC.

The role of somatostatin analogues in complete antiandrogen treatment in patients with prostatic carcinoma.

Somatostatin analogues (SMS-A) have been found to inhibit the growth of experimental tumors, as of prostate cancer, via several mechanisms as antihormonal and direct antimitogenic actions. It was demonstrated also that several SMS-A induce greater prostatic tumor regression with more pronounced histological changes if combined with LHRH analogues or in association with complete androgen blockade (CAB). In a phase II clinical trial we administered, in addition to CAB, SMS-A octreotide in 14 patients with stage D2 (group B) prostate cancer-8 previously hormonally treated (PHT) and 6 without any previous hormone treatment (NPHT); 4 other patients, 3 NPHT and one PHT, were treated with CAB only (group A). Antiandrogen and antitumoral activity followed assaying a) plasma testosterone b) prostatic specific antigen (PSA) c) prostatic acid phosphatase (PAP) levels and d) objective (o) and subjective (s) clinical improvement according to WHO criteria. Somatostatin activity was evaluated assaying Insulin like Growth Factor-1 (IGF-1) and Epidermal Growth Factor (EGF). In group B we observed 3 responses, with the best quality of response (oPR/sCR) among the 6 NPHT-patients (50%) and 3 responses among the PHT-patients (37,5%), two of them with an incomplete PHT. In group A, 2 out of 3 NPHT-patients had a response (oPR/sPR). Among group B patients we observed long symptom-free survival, when they responded (17 months), in comparison to group A patients (12 months), but almost the same total duration of survival in the two groups, 18.5 and 18 months, respectively. EGF and IGF-1 serum levels showed a distinct drop parallel to the decrease of PSA serum levels, among the patients with response vs. nonrespondent patients of group B during the treatment. Although our results showed that octreotide in small doses, in addition to CAB, having mild toxicity, enhance number, quality and perhaps the duration of symptom-free responses in patients with stage 2 prostate cancer, the therapeutic efficacy of this combined treatment remains to be ascertained in wider and better randomized clinical trials.

The use of 24-h ambulatory blood pressure monitoring (ABPM) during the first cycle of sunitinib improves the diagnostic accuracy and management of hypertension in patients with advanced renal cancer.

AIM: Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). PATIENTS AND METHODS: Normal 24-h ABPM at the baseline and at 2, 4 and 6 weeks of the first cycle was ensured with the successive use of hydrochlorothiazide+irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. RESULTS: Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. CONCLUSION: Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted.

Neuronal activity in posterior parietal area 7a during the delay periods of a spatial memory task.

1. Neuronal activity was recorded from area 7a of monkeys performing a delayed match-to-sample task requiring release of a behavioral key when a visual stimulus appeared at a remembered spatial location. 2. Activity in the delay periods was significantly elevated in 28% of 405 neurons studied and could be classified as either sustained or anticipatory in nature. 3. Sustained activity was characterized by maintained or slowly decreasing discharge rates that were typically greater when the preceding stimulus was at a location that evoked a strong response. Sustained activity was terminated when a subsequent stimulus appeared at another location. 4. Anticipatory activity was characterized by accelerating discharge rates that were ordinarily greater after a stimulus at a location that evoked a weak response. Anticipatory activity was often associated with facilitated responses to the next stimulus. 5. These data demonstrate that a population of neurons in area 7a is active during the delay periods of a spatial memory task that does not require a behavioral response directed toward the location of the stimulus. This activity could represent a short-term memory trace for the spatial location of the preceding stimulus.

Neurophysiological evidence for a role of posterior parietal cortex in redirecting visual attention.

Lesions of the posterior parietal cortex in humans and monkeys result in a spatial neglect syndrome characterized by defects in visual-spatial perception, oculomotor function, and directing visual attention. Although symptoms of spatial neglect can result from lesions to other cortical and subcortical areas, patients with posterior parietal lesions are particularly impaired in their ability to disengage and reorient visual attention. Neurophysiological experiments in area 7a of behaving monkeys reveal a large class of neurons that respond to visual stimuli and are powerfully modulated by states of attention. These cells respond better to passive visual stimuli presented during states of attentive fixation than to identical stimuli presented in nonattentive states. The responses of the majority of these cells are also influenced by covert shifts of attention away from the point of fixation; they respond to stimuli presented anywhere within their receptive fields except the covertly attended location. The combined effect of facilitation during attentive fixation and lack of response at the attended location results in a sensitivity for visual stimuli that appear at one location while attention is directed to another. The special sensitivity for unattended stimuli in this group of neurons in area 7a suggests that they may play a role in reorienting attention, possibly by providing signals of the spatial locations of novel stimuli.

Neuronal responses in area 7a to multiple-stimulus displays: I. neurons encode the location of the salient stimulus.

The primate posterior parietal cortex (PPC) plays an important role in representing and recalling spatial relationships and in the ability to orient visual attention. This is evidenced by the parietal activation observed in brain imaging experiments performed during visuo- spatial tasks, and by the contralateral neglect syndrome that often accompanies parietal lesions. Individual neurons in monkey parietal cortex respond vigorously to the appearance of single, behaviorally relevant stimuli, but little is known about how they respond to more complex visual displays. The current experiments addressed this issue by recording activity from single neurons in area 7a of the PPC in monkeys performing a spatial version of a match-to-sample task. The task required them to locate salient stimuli in multiple-stimulus displays and release a lever after a subsequent stimulus appeared at the same location. Neurons responded preferentially to the appearance of salient stimuli inside their receptive fields. The presence of multiple stimuli did not affect appreciably the spatial tuning of responses in the majority of neurons or the population code for the location of the salient stimulus. Responses to salient stimuli could be distinguished from background stimuli approximately 100 ms after the onset of the cue. These results suggest that area 7a neurons represent the location of the stimulus attracting the animal's attention and can provide the spatial information required for directing attention to a salient stimulus in a complex scene.

Neuronal responses in area 7a to multiple stimulus displays: II. responses are suppressed at the cued location.

Everyday visual scenes contain a variety of stimuli that vary in their significance. The companion paper demonstrates that neurons in the posterior parietal cortex (PPC) are capable of encoding the spatial locations of the salient stimulus in multiple stimulus scenes. The present experiment sought to address how neuronal responses to stimuli appearing in the receptive field are modulated after attention has been drawn to one of multiple stimuli in a visual scene. We recorded from area 7a of the PPC in monkeys trained to do a spatial version of a match-to-sample task. The results show that neuronal responses are greatly suppressed when stimuli appear at previously attended locations. No reduction in responsiveness is observed for locations where stimuli had previously appeared but did not draw attention. These results support the hypothesis that area 7a has a role in redirecting attention to stimuli appearing at novel, unattended locations.

Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory.

A conspicuous feature of cortical organization is the wide diversity of inhibitory interneurons; their differential computational functions remain unclear. Here we propose a local cortical circuit in which three major subtypes of interneurons play distinct roles. In a model designed for spatial working memory, stimulus tuning of persistent activity arises from the concerted action of widespread inhibition mediated by perisoma-targeting (parvalbumin-containing) interneurons and localized disinhibition of pyramidal cells via interneuron-targeting (calretinin-containing) interneurons. Moreover, resistance against distracting stimuli (a fundamental property of working memory) is dynamically controlled by dendrite-targeting (calbindin-containing) interneurons. The experimental observation of inverted tuning curves of monkey prefrontal neurons recorded during working memory supports a key model prediction. This work suggests a framework for understanding the division of labor and cooperation among different inhibitory cell types in a recurrent cortical circuit.

Covert attention suppresses neuronal responses in area 7a of the posterior parietal cortex.

1. The effect of covert attention was studied in area 7a of the posterior parietal cortex of rhesus monkeys performing a spatial match-to-sample task. The task required the animals to fixate a central target light, to detect and remember the location of a transient spatial cue, and to respond when one of a series of stimuli appeared at the cued location. Neuronal responses evoked by the visual stimuli were recorded during each behavioral trial. 2. Thirty-eight percent of the neurons isolated and studied in these experiments responded to visual stimuli. The responses of 55% of the neurons tested were suppressed, and 5% enhanced for stimuli presented at the attended location. Responses in the remaining neurons (40%) were unaffected by shifts in attention. 3. Activity in 57% of the suppressed neurons was reduced to rates not significantly different from spontaneous activity. 4. The extent of suppression for individual neurons was often restricted to the attended portion of the receptive field. 5. These data suggest a potential role for these neurons in the redirection of visual attention.

The role of acid and alkaline DNases as tumour markers in cancer of the genitourinary tract.

The levels of Acid and Alkaline DNases were measured in the serum of patients with: (a) Cancer of the Genitourinary Tract (confirmed by biopsy), (b) with inflammatory diseases and non-malignant tumours of the Genitourinary tract, (c) healthy blood donors. In the first group the results showed that the Acid DNase level was raised in 62% and Alkaline DNase in 43%. In the second group acid DNase was increased in 30% and Alkaline DNase in 13%. In the third group Acid and Alkaline DNase levels were normal. These results suggest that the measurement of Acid and Alkaline DNases could be considered as malignant diseases markers, in spite of false positive and false negative results in some cases.