Surgical treatment of high-risk prostate cancer.

High-risk prostate cancer (HRPC) currently comprises 17-35% of newly diagnosed cases and has the highest rate of metastasis and cancer-related death, making its management a top priority for improving prostate cancer outcomes. The definition of HRPC is not consensual and several risk stratification criteria have been used, which hinders the interpretation of data and the comparison of different studies. All classifications include prostate-specific antigen (PSA) level, biopsy Gleason score and clinical stage as criteria, but others have been added in an attempt to make stratification more accurate and clinically useful, to enable identification of the patients that can be cured by local treatment of the disease. HRPC was traditionally treated with radiotherapy (RT) and/or androgen deprivation therapy (ADT), but radical prostatectomy (RP) has slowly gained more importance in this context. This article aims to discuss the role of surgery in HRPC, highlighting the advantages of RP as primary treatment option: the ability to provide a definitive stage and grade of the cancer; allowing an early detection of treatment failure by having an undetectable PSA as treatment target; providing excellent local control of the disease; reducing the risk of metastatic progression to a greater extent than does RT. We will try to show the benefits and risks of a "surgery first" approach, keeping in mind that, despite the curative intent, a significant number of patients will still need adjuvant or salvage RT and/or ADT.

Laparoscopic pyeloplasty: status and review of literature.

The ideal treatment for ureteropelvic junction (UPJ) obstruction should have the highest success rate, enable treatment of all types of obstruction, allow removal coexisting renal stones, and be minimally invasive. Open pyeloplasty offers all these features except the last (minimal invasiveness), whereas endourology techniques guarantee only the last one. Different techniques of pyeloplasty can be applied laparoscopically, although the best results are seen with dismembered pyeloplasty (Anderson-Hynes technique). Various methods of tissue approximation have been devised to avoid the difficult-to-master, time-consuming conventional suturing technique. Laparoscopic (antegrade) stenting is preferred by some surgeons, but we consider retrograde stenting is superior, as this rules out the presence of associated distal-ureteral obstruction. The transperitoneal approach has the advantages of a larger working space and readily identifiable anatomic landmarks. However, access to the renal pelvis requires considerable mobilization and retraction of the overlying loops of bowel. The retroperitoneal approach has the perceived disadvantage of a somewhat limited working space and absence of readily identifiable intra-abdominal anatomic structures such as the liver and spleen. However, the retroperitoneal approach has the advantage of greater familiarity, better detection of crossing vessels, direct and rapid access to the UPJ, and less risk of ileus. The robot-assisted technique has made suturing easier and may allow expansion of advanced laparoscopic procedures to surgeons without expertise in advanced laparoscopic surgery. The optimal length of follow-up after pyeloplasty is still unclear. Although most failures occur within the first 2 years, failures continue to appear after 5 and 10 years.

High fat diet induced hepatic insulin resistance is not related to changes in hypothalamic mRNA expression of NPY, AgRP, POMC and CART in mice.

The hypothalamic circuitry, apart from its impact on food intake, modulates insulin sensitivity to adapt metabolic conditions in the face of environmental fluctuations in nutrient availability. The purpose of the present study was to investigate the effects of 2 weeks high fat feeding in wildtype mice on (1) insulin sensitivity and triglyceride accumulation in liver and muscle in relation to (2) mRNA expression levels of Neuropeptide Y (NPY), Agouti-related protein (AgRP), pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. Two weeks of high fat feeding induced hepatic insulin resistance in the presence of increased hepatic triglyceride accumulation. In muscle, however, 2 weeks of high fat feeding did not result in changes in insulin sensitivity or in triglyceride content. mRNA expression levels of NPY, AgRP, POMC, and CART in the hypothalamus were not different between the groups. This study shows that 2 weeks of high fat feeding in mice does not affect mRNA expression levels of NPY, AgRP, POMC or CART, in the whole hypothalamus, despite induction of hepatic, but not peripheral, insulin resistance. Therefore, a major physiological role of these neuroendocrine factors in the induction of hepatic insulin resistance during a high fat diet seems less likely.

Heterotopic Cortical Afferents to the Medial Prefrontal Cortex in the Rat. A Combined Retrograde and Anterograde Tracer Study.

Cortical afferent projections towards the medial prefrontal cortex (mPFC) were investigated with retrograde and anterograde tracer techniques. Heterotopical afferent projections to the medial prefrontal cortex arise in secondary, or higher order, sensory areas, motor areas and paralimbic cortices. On the basis of these projections three subfields can be discriminated within the mPFC. (1) The ventromedial part of mPFC, comprising the pre- and infralimbic areas, receives mainly projections from the perirhinal cortex. (2) The caudal two-thirds of the dorsomedial PFC, comprising frontal area 2 and the dorsal anterior cingulate area, receives projections from the secondary visual areas, the posterior agranular insular area and the retrosplenial areas. (3) The rostral one-third of the dorsomedial PFC is the main recipient of projections from the somatosensory and motor areas and the posterior agranular insular area. The laminar distribution of cells projecting to the mPFC varies considerably in the different cortical areas, just as the laminar distribution of termination of their fibres within the mPFC does. It is concluded that the corticocortical connections corroborate with subcortical connectivity in attributing to the mediodorsal projection cortex of the rat functions which are comparable to those of certain prefrontal, premotor and anterior cingulate areas in the monkey.

Development of connections between the mediodorsal nucleus of the thalamus and the prefrontal cortex in the rat.

The postnatal ingrowth of thalamocortical fibers from the mediodorsal nucleus to the prefrontal cortex was investigated in relation to the development of cortical lamination. Like the dopaminergic fibers in the prefrontal cortex and the thalamic fibers in the visual cortex, the mediodorsal fibers have entered the prefrontal cortex at birth. Most of the fibers are found in the developing layer VI, but, in contrast to the above-mentioned systems, a considerable number of mediodorsal fibers have already penetrated into the upper, most immature part of the cortical plate on postnatal day 1. From day 1 to day 7 an increasing number of mediodorsal fibers reach the upper cortical plate, which by then is developing layer III, the terminal layer of these fibers. The reciprocal connection from the layer VI cells of the prefrontal cortex to the mediodorsal nucleus develops between day 4 and day 9. Finally, the projection from the contralateral prefrontal cortex to the mediodorsal nucleus is established around day 10. The early presence of the mediodorsal fibers in the upper, differentiating cortical plate might indicate an important role for the mediodorsal fibers in the laminar development of the prefrontal cortex.

Cytoarchitectonic development of the prefrontal cortex in the rat.

This paper gives an account of the cytoarchitectonic characteristics that make it possible to delineate, from as early as day 6, different subareas of the prefrontal cortex of the rat. Three phases can be distinguished during postnatal development. The first phase (from day 1 until day 18) is dominated by differentiation of the neurons within the cortical plate and by the formation of the cortical layers. At day 1, regional differences are observed in the cytoarchitecture of the cortical plate which correspond to the future subareas of the prefrontal cortex. The formation of layer IV occurs in the dorsolateral cortex around day 6, and from this age the agranular prefrontal cortex is well demarcated from the other parts of the frontal cortex. Between day 6 and day 10, the cortical plate has disappeared and all cortical layers can be recognized in the prefrontal cortex. Differentiation of the cells within the cortical layers changes the cytoarchitectonic character of the layers through day 18. During the second phase (from day 18 until day 30) little change occurs in the cytoarchitectonic characteristics of the prefrontal subareas. During the third phase (from day 30 until day 90) the delineation of the cortical layers becomes less clear in Nissl-stained sections, and the individual cytoarchitectonic variance increases. On the basis of cytoarchitectonic criteria it can be concluded that the orbital prefrontal cortex develops earlier than does the medial prefrontal cortex.

Postnatal volumetric development of the prefrontal cortex in the rat.

The medial and orbital parts of the prefrontal cortex (PFC) increase in volume during the first weeks of postnatal life. At the end of this period, however, the volumes of both parts of the PFC reach a significantly higher value than in adulthood. Subsequently the volumes decrease until the adult volume is attained. The three subareas of the medial PFC (i.e., the medial precentral area, the dorsal anterior cingulate, and the prelimbic area) reach a maximum volume around day 24, while the two orbital PFC subareas (i.e., the dorsal and ventral agranular insular areas) attain their maximum value around day 30. The differences found in the growth pattern of the five PFC subareas, which are innervated by specific subnuclei of the mediodorsal nucleus of the thalamus, suggest a role of these subnuclei in the PFC development.

Prenatal development of neurons in the human prefrontal cortex. II. A quantitative Golgi study.

The quantitative development of neurons in the human dorsolateral and lateral prefrontal cortex was studied in Golgi-impregnated tissue from postmortem brains ranging from 13.5 weeks of gestation up to the second postnatal month. Pyramidal neurons in the future layers III and V of the cortical plate, as well as different types of neurons in the transient subplate zone, were studied. The basal dendrites of the future layer III and V pyramidal neurons show a slow increase during the first two-thirds of the period of gestation. From 27-32 weeks of gestation on, there is a rapid increase in the length of basal dendrites of layer III and V pyramidal neurons, while the number of basal dendrites per pyramidal neuron appears to stabilize at 26/27 weeks of gestation. The increase in total length of basal dendrites per pyramidal neuron is mainly due to an increase in the number of bifurcations and the growth of terminal segments. Throughout the whole period studied, the size of the layer III pyramidal basal dendritic tree was smaller than that of layer V pyramidal neurons. Thus, not until postnatal life do the layer III pyramidal basal dendrites become larger than those of layer V. No statistically significant differences were found for data of the pyramidal neurons between the superior and middle frontal gyri. The dendritic size of subplate neurons, except for the subplate inverted pyramidal neurons, significantly exceeds the size of the basal dendrites of the pyramidal neurons up to the seventh gestational month, which indicates an earlier maturation of these subplate neurons. During the period examined, no clear decrease in the size of the subplate neurons was observed. The present study shows that the dendritic parameters of either subplate or cortical plate pyramidal neurons rapidly increase during the periods of ingrowth of afferent fibers into the subplate zone and cortical plate, respectively. In the Golgi preparations of the prefrontal cortex, the size of the subplate neurons does not show any clearly regressive changes at the end of the prenatal period.

Prenatal development of neurons in the human prefrontal cortex: I. A qualitative Golgi study.

Golgi-Stensaas and rapid-Golgi staining techniques are used to study neuronal differentiation in the developing human prefrontal cortex in fetuses, premature infants, and full-term newborns from 10.5 to 40 weeks of gestation. Horizontal neurons (Cajal-Retzius neurons) above the cortical plate (in the marginal zone) and randomly oriented neurons below the cortical plate (in the primordial subplate) are more differentiated than the immature bipolar cortical plate neurons in the 10.5-week fetus. During 13.5-15 weeks of gestation the fetal subplate zone can be clearly distinguished-between the cortical plate and the intermediate zone. This subplate zone contains more mature neurons than the cortical plate, especially polymorphous neurons. The basic features of the apical and basal dendrites of pyramidal neurons develop between 17 and 25 weeks of gestation, before the thalamocortical fibres invade the cortical plate. Intensive differentiation of the subplate neurons occurs in this period, when various types of afferent fibres reside in the subplate zone. At least five neuronal types can be distinguished in the subplate, i.e., polymorphous, fusiform, multipolar, normal, and inverted pyramidal neurons. The ingrowth of afferent fibres into the cortical plate between 26 and 34 weeks of gestation coincides with intensive dendritic differentiation and the appearance of spines on dendrites of the prospective layer III and V pyramidal neurons as well as with the differentiation of the double bouquet interneurons in the prospective supragranular layers and layer IV. Multipolar nonpyramidal neurons with the dendritic features of basket neurons are observed between 32 and 34 weeks of gestation in future layer V. They are less differentiated than the double bouquet neurons. The neurons of the subplate zone continue their dendritic differentiation after 26/27 weeks of gestation and are still observed in the full-term newborn. The axonal pattern of the subplate neurons suggests a possible functional role for them as either interneurons or projection neurons.

Prenatal development of GABA-ergic neurons in the neocortex of the rat.

The present study shows that in the prenatal rat neocortex the GABA immunoreactive neurons are not limited to the marginal, subplate, and intermediate zones, but are also found in all fetal zones of the cerebral anlage. The first GABA-ergic cells are observed on embryonic day 14 in the plexiform primordium. On embryonic day 15, a second population of GABA-ergic cells is observed in the intermediate zone. Beginning on day 16 of gestation and continuing throughout gestation, GABA-ergic neurons are observed in the marginal zone, the subplate zone, the cortical plate, and the ventricular and subventricular zones. Furthermore, while the number of GABA-ergic cells in the cortical plate increases, GABA-ergic neurons in the intermediate zone and subventricular zone decrease in number after embryonic day 19.

Morphology of neurons in the basal forebrain nuclei of the rat: a Golgi study.

The neuronal cell types and their morphology in the nucleus basalis (NB), in the horizontal and vertical limbs of the diagonal band of Broca (NHL and NVL), and in the medial septal nucleus (MSN) were examined in Golgi-impregnated material. Cells appeared as multipolar or oligopolar and displayed a variable dendritic morphology; their somata varied considerably both in shape and size. The dendrites of most cells were restricted within nuclear boundaries, although occasionally neurons located near boundaries, particularly cells in NHL, extended dendritic arbors into neighboring areas. Axons were rarely seen, but when they were found they were generally not impregnated beyond the initial segment and displayed no apparent preferential direction. Three types of cells common to each of the 4 nuclear groups could be identified on the basis of soma shape and dendritic form. The first type included large multipolar neurons with triangular or polygonal perikarya and typically 3-5 dendrites emerging from the poles of each cell. These cells were especially numerous in NB, NHL, and NVL, but were much less frequent in MSN. The second type comprised medium-sized cells with round or oval somata and a small number, usually 2-3, of dendrites. They constituted a large percentage of the cell population in MSN, but were also encountered in NHL and NVL as well as in NB. The third type consisted of cells with fusiform or spindle-shaped somata with usually single dendrites emanating from each pole of the cell. A rare but distinct type of spindle-shaped neuron with dendrites bearing a rich complement of long and thin appendages was observed mainly in the ventral border of NHL. The present observations suggest that although the proportions and sizes of the 3 types of neurons vary between the 4 nuclei, neurons throughout the basal forebrain share common morphological characteristics.

Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level.

In the present study the dopaminergic innervation of the prefrontal cortex was studied by means of a recently developed anti-dopamine serum. This method can demonstrate endogenous dopamine in a specific way, and offers the opportunity to study the distribution of dopaminergic fibres in the cortex in detail in counterstained sections. Furthermore, dopaminergic nerve endings can be visualized at the electron microscopic level. Light microscopic observations demonstrated that the highest density of dopaminergic fibres in the frontal cortex is found in the prefrontal cortex and the infralimbic cortex. Within the prefrontal cortex, a good correlation is found between regional differences in distribution of dopaminergic fibres and the cytoarchitectonic parcellation of this part of the cortex. Outside the prefrontal cortex dopaminergic fibres were observed in adjacent frontal areas, the cortex surrounding the entire rhinal sulcus and the retrosplenial cortex. Electron microscopic observations demonstrated dopaminergic terminals through all cortical layers. The majority of dopaminergic terminals in the prefrontal cortex from synaptic contacts with dendritic processes. The synaptic profiles were usually symmetric and were characterized by the presence of many clear vesicles and an occasional dense-core vesicle.

The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system.

The biological clock, the suprachiasmatic nucleus (SCN), is essential for our daily well-being. It prepares us for the upcoming period of activity by an anticipatory rise in heart rate, glucose and cortisol. At the same time the 'hormone of the darkness', melatonin, decreases. Thus, the time-of-day message penetrates into all tissues, interestingly not only by means of hormones but also by a direct neuronal influence of the SCN on the organs of the body. The axis between the SCN and the paraventricular nucleus of the hypothalamus (PVN) is crucial for the organization/synchronization of the neuroendocrine and autonomic nervous system with the time of day. This SCN-neuroendocrine PVN axis takes care of a timely hormonal secretion. At the same time, the SCN-autonomic PVN axis fine-tunes the organs by means of the autonomic nervous system for the reception of these hormones. Finally, the similar organization of the projections of the human SCN as compared with that in the rodent brain suggests that these basic principles of neuroendocrine autonomic interaction may also be true in the human. The physiological data collected in humans thus far seem to support this hypothesis, while pathological changes in the SCN of humans suffering from depression or hypertension indicate a role for the SCN in the etiology of these diseases.

Developmental pattern of NADPH-diaphorase activity and nitric oxide-stimulated cGMP immunoreactivity in the frontal rat cortex and its role in functional recovery from aspiration lesions.

The present study was undertaken to (1) explore the cortical nitric oxide (NO)-system during postnatal development and (2) to see whether or not the NO-system reacts differentially after neonatal and adult lesions of the medial prefrontal cortex. Three aspects of the NO-system were studied, i.e., NADPH-diaphorase (NADPH-d) activity, sodium nitroprusside (SNP)- and N-methyl-D-aspartate (NMDA)-stimulated cGMP-immunoreactivity (cGMP-IR). It was shown that: (1) the development of NADPH-d activity containing cells is continued in the period from P6 until P21; (2) during the same period, large developmental changes take place in basal, and SNP- or NMDA-stimulated cGMP-IR in the cortex. These changes are regionally specific and follow the general cortical developmental pattern; and (3) aspiration lesions do not induce major changes in the distribution of NADPH-d activity or cGMP-IR, either basal, SNP- or NMDA-stimulated.

Acquisition of conditional associations and operant delayed spatial response alternation: effects of lesions in the medial prefrontal cortex.

In this article 8 male Wistar rats received bilateral lesions of the medial prefrontal cortex, whereas another 8 rats were control operated. Three weeks after surgery, they were exposed to an autoshaping procedure in which the insertion of a lever into the experimental chamber (conditioned stimulus) always preceded the delivery of a response-independent food pellet (unconditioned stimulus). Subjects with lesions acquired this conditional association faster than control-operated subjects as evidenced by the fact that they were more likely than control-operated subjects to contact the conditioned stimulus at higher rates. Locomotor activity, observed in a standard open-field preceding autoshaping sessions, decreased for both groups of subjects with repeated exposure to the open-field, whereas differences between groups were not observed. The same subjects were also exposed to an operant delayed spatial response alternation procedure in which they were required to alternate responding between two levers that were inserted into the experimental chamber after delay intervals of either 5, 10, or 20 s had elapsed. Alternation response accuracy of both subjects with lesions and control subjects decreased as a function of the duration of the delay interval, but control-operated subjects responded more accurately than did lesion subjects at each interval duration. Response accuracy increased with prolonged training for both groups of subjects, but faster for control-operated than for subjects with lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphometry of size/volume variables and comparison of their bivariate relations in the nervous system under different conditions.

Comparison of the different approximation equations and procedures to estimate the volume of a brain region with an irregular shape contained in parallel sections indicates that the 'basic volume estimator' using systematic section is very efficient and sufficiently accurate. Important in estimating the volume is the correction for shrinkage and the accuracy of the section thickness determination. Methods to estimate thickness of section are outlined, and the method of differential focusing is discussed. In the Appendix, the corrections are described for overestimation of the volume by overprojection of the cross-sectional area and underestimation by underprojection when the size of cross-sectional area changes non-negligibly within sections. Statistical techniques to compare bivariate linear relations of different groups are reviewed. Emphasis is laid on Model II regression techniques that are used when the two variables considered are both subject to biological variation and measurement error. A new Model II procedure is proposed to compare the coincidence of the slopes of bivariate distributions and to test whether or not an experimental bivariate sample deviates significantly from a control sample when only the control group shows a significant bivariate linear relationship.

Comparison of the effects of neonatal and adult medial prefrontal cortex lesions on food hoarding and spatial delayed alternation.

Performance in food hoarding, a species-typical task, and spatial delayed alternation, a learning task, was investigated in male rats with bilateral medial prefrontal cortex (mPFC) lesions sustained in adulthood or at the age of 6 days. Animals with adult mPFC lesions hoarded significantly fewer food pellets than their controls. The mPFC lesion effect on hoarding behaviour of the neonatally operated rats was unclear because of the unexpectedly low hoarding score of their controls. In the spatial delayed alternation task, the animals with mPFC lesions in adulthood exhibited a permanent deficit, while the animals with neonatal mPFC lesions showed no significant deficits. It is concluded that a bilateral lesion in adulthood, mainly affecting the frontal area 2 and the dorsal anterior cingulate area of the mPFC, results in a permanent deficit in food hoarding and spatial delayed alternation performance, whereas a similarly restricted mPFC lesion at the age of 6 days shows a complete sparing of the spatial delayed alternation task performance.

Sex-difference and left-right asymmetries in the prefrontal cortex during postnatal development in the rat.

Left over right asymmetries in volume have been found in two subareas of the medial prefrontal cortex (PFC), and a right over left in the orbital PFC. The asymmetries change during development, indicating differential growth rates for left and right PFC parts. The asymmetry of the medial PFC reached significance from day 10 until day 18 and at day 90. The asymmetry of the orbital PFC reached significance from day 30 until day 60. At day 90 no significant asymmetry is demonstrated in this part of the PFC. A significant sexual dimorphism was demonstrated for the dorsal agranular insular subarea (AId) in the orbital PFC.

Activation of mesocortical dopaminergic system in the rat in response to neonatal medial prefrontal cortex lesions. Concurrence with functional sparing.

Neonatal lesions of the medial part of the rat prefrontal cortex (mPFC) (performed at the age of 6 days) resulted in a sparing in the performance of spatial delayed alternation (SDA) and an increase in dopaminergic (DA) innervation. The increased DA innervation was primarily observed in the remaining part of the mPFC. The DA fibre density was considerably higher in the non-ablated part of the mPFC, and the fibres were thicker with more large varicosities compared with sham-operated controls. Biochemical measurements showed a 3.5-fold increase in DA concentration in the remaining part of the mPFC of the animals with neonatal lesions when compared with the mPFC of sham-operated animals. In addition the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased. The metabolite/transmitter ratios, indicating DA utilisation, did not significantly differ from controls. The increased DA innervation and the increased concentration of DA and its metabolites in the animals with neonatal lesions further support our hypothesis that the mesocortical DA system is involved in the neural mechanism of sparing of function observed after neonatal mPFC lesions. However, sparing of function in animals with no discernable mPFC forces us to conclude that this DA response cannot be the only factor involved in the mechanism of sparing of function.

Neuroanatomical correlates of sparing of function after neonatal medial prefrontal cortex lesions in rats.

In rats, the possibility of neuroanatomical changes in response to partial medial prefrontal cortex lesions at postnatal day 6, concomitant with behavioural sparing, was investigated. The projections from the mediodorsal nucleus of the thalamus (MD) and the mesocortical dopaminergic (DA) projection were examined. No indications were found for a changed pattern of projection from MD in response to either a neonatal or an adult medial prefrontal cortex (mPFC) lesion. However, the DA innervation was changed after neonatal mPFC lesions. In the remainder of the mPFC, the DA fibre network proved to be denser, fibres were thicker, had more varicosities, and often the background staining was higher. None of these phenomena were seen in operated adult rats or in controls. It is postulated that the changes in DA innervation might contribute to the sparing of function observed in the spatial delayed alternation task.