Conversion to a sirolimus-based regimen is associated with lower incidence of BK viremia in low-risk kidney transplant recipients.

BACKGROUND: BK viral nephropathy is an increasingly recognized cause of early allograft loss in kidney transplantation. This study aimed to determine whether a sirolimus (Sir)-based calcineurin inhibitor-sparing regimen is associated with a lower incidence of BK viremia. METHODS: This was a single-center retrospective study. Patients were either on tacrolimus (Tac)-based or on Sir-based immunosuppression. Conversion from Tac to Sir occurred at or after 3 months if patients were <62 years of age, had calculated panel reactive antibodies of <20%, and did not have acute early rejection. RESULTS: Incidence of clinically significant BK viremia was 17.9% in the Tac group and 4.3% in the Sir group. Cox regression multivariate analysis showed that male gender (hazard ratio [HR] = 2.87) and switch to Sir (HR = 0.333) impacted the incidence of BK viremia. Kaplan-Meier analysis showed a higher BK-free survival in the Sir group. A trend was seen toward shorter time to resolution of BK viremia and lower peak viremia in the Sir group. Patients on Sir had a higher estimated glomerular filtration rate at each time point; 34% of patients discontinued Sir because of side effects. CONCLUSION: Conversion to Sir-based maintenance immunosuppression at or about 3 months after kidney transplantation correlates with a lower incidence of BK viremia.

Recommendations for the assessment and reporting of multivariable logistic regression in transplantation literature.

Multivariable logistic regression is an important method to evaluate risk factors and prognosis in solid organ transplant literature. We aimed to assess the quality of this method in six major transplantation journals. Eleven analytical criteria and four documentation criteria were analyzed for each selected article that used logistic regression. A total of 106 studies (6%) out of 1,701 original articles used logistic regression analyses from January 1, 2005 to January 1, 2006. The analytical criteria and their respective reporting percentage among the six journals were: Linearity (25%); Beta coefficient (48%); Interaction tests (19%); Main estimates (98%); Ovefitting prevention (84%); Goodness-of-fit (3.8%); Multicolinearity (4.7%); Internal validation (3.8%); External validation (8.5%). The documentation criteria were reported as follows: Selection of independent variables (73%); Coding of variables (9%); Fitting procedures (49%); Statistical program (65%). No significant differences were found among different journals or between general versus subspecialty journals with respect to reporting quality. We found that the report of logistic regression is unsatisfactory in transplantation journals. Because our findings may have major consequences for the care of transplant patients and for the design of transplant clinical trials, we recommend a practical solution for the use and reporting of logistic regression in transplantation journals.

Functional organization of lateral geniculate cells following removal of visual cortex in the newborn kitten.

When the visual cortex of a newborn kitten is removed, most neurons in the dorsal lateral geniculate nucleus degenerate, but a small population of large cells is spared. Electrophysiological recording revealed that detailed visual topography in the nucleus is abnormal and that single cells have unusually large receptive fields. These results suggest that optic axons deprived of their normal synaptic targets rearrange their connections to converge on local surviving neurons.

Lateral geniculate nucleus in dark-reared cats: loss of Y cells without changes in cell size.

In cats reared in the dark from birth until 4 months of age, the dorsal lateral geniculate nucleus contained few normal Y cells in either the binocular or monocular segments. Although most of the neurons appeared to be normal X cells unaffected by light deprivation, many cells with abnormal receptive field and response charcteristics were encountered. These effects were permanent, since 1 to 2 years of normal visual experience following initial light deprivation did not lead to any functional recovery. The sizes of cell bodies in cats reared in the dark were similar to those of normal animals, an indication that changes in geniculate cell physiology need not be related to changes in cell size.

Eye-head coordination in monkeys: evidence for centrally patterned organization.

Eye-head coordination was investigated by recording from the neck and eye muscles in monkeys. The results show that (i) during eye-head turning, neural activity reaches the neck muscles before the eye muscles, and (ii) all agonist neck muscles are activated simultaneously regardless of the initial head position. Since overt movement of the eyes precedes that of the head, it was concluded that the central neural command initiates the eye-head sequence but does not specify its serial order. Furthermore, it was determined that the compensatory eye movement is not initiated centrally but instead is dependent upon reflex activation arising from movement of the head.

Anomalous retinal pathways in the Siamese cat: an inadequate substrate for normal bioncular vision.

All major retinal pathways in the Siamese cat are abnormal, with almost total crossing of the projections to the pretectum and superior colliculus. These projections represent a marked disruption in the customary neural substrate for binocular vision, which implies a consequent impairment in stereoscopic depth perception. Crossed eyes, commonly seen in the Siamese cat, may therefore arise from a neuroanatomical defect in the primary visual pathways.

Loss of retinal X-cells in cats with neonatal or adult visual cortex damage.

Recordings were made from single retinal ganglion cell somas in cats whose visual cortical areas 17 and 18 were damaged on the day of birth or in adulthood. Neonatal lesions produced a 78 percent loss of X-cells in the retina, while lesions made in adulthood produced a 22 percent loss. Y-cells and W-cells were unaffected. This retinal abnormality needs to be considered when interpreting studies of behavioral deficits and neural mechanisms of recovery after damage to the visual cortex.

A randomized, double-blind, and placebo-controlled study with tranexamic acid of bleeding and fibrinolytic activity after primary coronary artery bypass grafting.

Cardiopulmonary bypass is frequently associated with excessive blood loss. Platelet dysfunction is the main cause of non-surgical bleeding after open-heart surgery. We randomized 65 patients in a double-blind fashion to receive tranexamic acid or placebo in order to determine whether antifibrinolytic therapy reduces chest tube drainage. The tranexamic acid group received an intravenous loading dose of 10 mg/kg, before the skin incision, followed by a continuous infusion of 1 mg kg(-1) h(-1) for 5 h. The placebo group received a bolus of normal saline solution and continuous infusion of normal saline for 5 h. Postoperative bleeding and fibrinolytic activity were assessed. Hematologic data, convulsive seizures, allogeneic transfusion, occurrence of myocardial infarction, mortality, allergic reactions, postoperative renal insufficiency, and reopening rate were also evaluated. The placebo group had a greater postoperative blood loss (median (25th to 75th percentile) 12 h after surgery (540 (350-750) vs 300 (250-455) mL, P = 0.001). The placebo group also had greater blood loss 24 h after surgery (800 (520-1050) vs 500 (415-725) mL, P = 0.008). There was a significant increase in plasma D-dimer levels after coronary artery bypass grafting only in patients of the placebo group, whereas no significant changes were observed in the group treated with tranexamic acid. The D-dimer levels were 1057 (1025-1100) microg/L in the placebo group and 520 (435-837) microg/L in the tranexamic acid group (P = 0.01). We conclude that tranexamic acid effectively reduces postoperative bleeding and fibrinolysis in patients undergoing first-time coronary artery bypass grafting compared to placebo.

Late outcome of unsupported annuloplasty for rheumatic mitral regurgitation.

OBJECTIVES: The aim of this study was to evaluate medium- and long-term (range 4 months to 17 years) clinical results in a series of patients treated surgically by unsupported mitral annuloplasty. BACKGROUND: Mitral valve regurgitation has usually been treated by valve replacement or ring annuloplasty. A few series have reported plastic repair procedures without annular support or remodeling. Furthermore, in rheumatic lesions the results have been inferior to those in degenerative mitral insufficiency, and the majority of previous reports have provided information on short- or medium-term follow-up. METHODS: One hundred fifty-four patients were operated on (55 male [36%] and 99 female [64%]). The mean age +/- SD was 36 +/- 16 years (range 5 to 73). Associated lesions comprised 47 aortic and 21 tricuspid valve lesions and 2 atrial septal defects. Patients with concomitant mitral stenosis were not included. Preoperative functional class was I or II in 19% and III or IV in 81%. The cardiothoracic ratio was 0.61 +/- 0.10. All patients underwent an unsupported mitral annuloplasty procedure in which the mural portion of the annulus was reduced by applying two buttressed mattress sutures at the commissures without compromising the width of the septal leaflet. When necessary, additional chordal procedures were performed. No patients received ring or posterior annular support. RESULTS: The early mortality rate was 1.9% (three patients; one of the three died of myocardial failure and two of pulmonary thromboembolism). The late mortality rate was 5.8% (nine patients; three of the nine died of myocardial failure, one each of septicemia, pulmonary thromboembolism and sudden arrhythmic death and three of unknown causes). Twenty-eight patients (18.2%) were reoperated on because of mitral valve dysfunction and 2 (1.3%) because of prosthetic aortic valve dysfunction. A residual late systolic murmur was present in 48% of patients. Late complications were systemic thromboembolism in 5.8% (one third with an aortic valve prosthesis), infective endocarditis in 1.3% and pulmonary thromboembolism in 0.6%. Postoperative functional class was I or II in 84% and III or IV in 16%. Cardiothoracic ratio was 0.58 +/- 0.10. Actuarial probability of late survival was 79.5 +/- 5.3% at 10 years and 71.0 +/- 7.4% at 14 years. Event-free survival was 67.9 +/- 8.9% at 10 years and 56.1 +/- 11.7% at 14 years. CONCLUSIONS: Rheumatic mitral regurgitation can be effectively treated by annuloplasty without prosthetic annular support, with late results comparable to those obtained with more complicated procedures. This observation is particularly important for treatment of children and young adult patients.

Development of the dorsal lateral geniculate nucleus in the cat.

The development of the lateral geniculate nucleus has been studied systematically in Nissl preparations from a series of cats that ranged in age from newborn to adult. In addition, preliminary observations are reported at two stages of fetal development. It was found that laminae develop in the lateral geniculate nucleus near the time of birth and continue to differentiate during the first postnatal week. During development the major axis of the lateral geniculate rotates approximately 180 degrees in the sagittal plane. The rotation begins prenatally and is not completed until after the twentieth postnatal week. The volume of the lateral geniculate was computed at different ages and it was determined that during the first postnatal month the nucleus attains two-thirds of its adult size. However, the rate of growth declines markedly thereafter, and final volume, like final position, is not achieved until late in development. The cross-sectional areas of lateral geniculate neurons were measured at four locations in the nucleus in each animal. The locations represented the following parts of the visual field: the paracentral and inferior peripheral fields in the binocular segment of lamina A; the monocular segment of lamina A; and the paracentral field in lamina A1. Neurons in each of these locations grow at approximately the same rate and are essentially fully grown by 56 days. Cell size histograms show that more large cells are found in lamina A1 and more small cells in the monocular segment than elsewhere in the dorsal laminae. Unlike the retina, there appears not to be a gradient of development in the lateral geniculate nucleus from center to periphery, at least in terms of cell body size at the ages studied. On the contrary, that part of the lateral geniculate nucleus which represents the paracentral visual field is the last segment in the dorsal laminae to achieve a mature cell size distribution. Finally, a discrete class of small spindle-shaped neurons was observed in the lateral geniculate nucleus ventral and caudal to the C laminae during the first two postnatal weeks. These cells possess a leading and trailing cytoplasmic process and are distinctly different from cells in the main laminae. It is suggested that these spindle-shaped cells may be neurons that are still in the process of migration or differentiation in the postnatal animal.

Synaptic reorganization in the dorsal lateral geniculate nucleus following damage to visual cortex in newborn or adult cats.

We have studied the effects of making large lesions of visual cortex on the synaptic organization of the dorsal lateral geniculate nucleus (LGN) in the cat. Visual cortex was removed at birth in one group of cats and during adulthood in a second group. Following survival periods of 6 months to 2 years, the organization of synapses made by afferents from the retina in the LGN was investigated quantitatively with the electron microscope. In single thin sections we determined the percentage of retinal axon terminals that made synapses in the LGN, the average number of synapses made by each retinal axon terminal, and the identity of each postsynaptic process. These measurements were made separately for retinogeniculate connections in the A and C laminae of the LGN. For comparison, similar sets of measurements were made in adult cats that had been reared normally. When single thin sections from the A or C laminae of the LGN in normal cats are examined, about 60% of the axon terminals from the retina are seen to make at least one synaptic contact. These contacts can be with dendrites or F profiles or both. On average, each retinogeniculate terminal makes approximately 1.4 synapses in the plane of a single section and contacts dendrites three times as often as F profiles. In the A laminae of the LGN in cats that received a visual cortex lesion at birth or in adulthood, the percentage of retinal terminals that make synapses is the same as in normal cats. Similarly, the average number of synaptic contacts made by each retinogeniculate terminal is not changed by a lesion of visual cortex. In contrast, the number of contacts made with dendrites is reduced markedly, by about 29% after a lesion at birth and 53% after a lesion as an adult. However, these reductions are offset by compensatory increases in the number of contacts made with F profiles, and thus the mean number of contacts made by each retinogeniculate terminal is stabilized at a normal value. In the C laminae of the LGN, retinogeniculate terminals also reapportion their synaptic contacts. In cats with a lesion during adulthood, the redistribution of synapses is compensatory, as in the A laminae. When a lesion is made at birth, however, the number of new retinal contacts made with F profiles exceeds the number of dendritic contacts that are lost. As a result, each retinogeniculate terminal makes about 26% more synapses, in total, than normal.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of corticogeniculate synapses in the cat.

The development of corticogeniculate synapses was studied in 16 cats ranging in age from newborn to adult. Tritiated proline was injected into areas 17 and 18 of the visual cortex in order to label corticogeniculate terminals in lamina A of the dorsal lateral geniculate nucleus. The labeled terminals were then characterized ultrastructurally using electron microscopic autoradiography. Labeled synaptic profiles were found in newborn kittens, indicating that corticogeniculate connections are present in the cat at birth. Morphologically, however, many corticogeniculate endings in newborn and 1-week-old kittens are different from those in older animals in that they do not form well-defined terminal boutons, and their synaptic vesicles are often loosely packed. In kittens 2 weeks of age and older, corticogeniculate axons end as RSD terminals exclusively; i.e., they are relatively small in size and contain round, densely packed synaptic vesicles, and occasionally an electron-dense mitochondrion (Guillery: Z. Zellforsch. 99: 1-38, '69). However, not all RSD terminals in the LGN represent input from visual cortex. Injections of 3H-proline into the mesencephalic reticular formation also label RSD terminals selectively in the lateral geniculate nucleus. At all ages corticogeniculate axons make synaptic contacts with dendrites exclusively, and they are always presynaptic. This suggests that the essential pattern of corticogeniculate synapses is formed early and is not altered during subsequent development. Quantitatively, there is no significant change in the size of corticogeniculate terminals or their synaptic vesicles in kittens 2 weeks of age (the youngest measured) and older. In contrast, the synaptic contact lengths of these terminals decreases about 28% between 2 and 12 weeks. During this same period there is approximately a twofold increase in the density of corticogeniculate terminals in the neuropil of lamina A. Since the volume of neuropil in lamina A increases almost fourfold between 2 and 12 weeks, the doubling of corticogeniculate terminal density represents about an eightfold increase in terminal number. After 12 weeks there is little change in the length, density, or number of corticogeniculate synaptic contacts, which suggests that the morphological development of the corticogeniculate pathway is essentially complete by this age.

Axotomy-induced neuronal death and reactive astrogliosis in the lateral geniculate nucleus following a lesion of the visual cortex in the rat.

Following a unilateral lesion of the visual cortex (cortical areas 17, 18, and 18a) in adult rats, neurons in the ipsilateral dorsal lateral geniculate nucleus (LGN) are axotomized, which leads to their atrophy and death. The time course of this neuronal degeneration was studied quantitatively, and the astroglial response was examined with glial fibrillary acidic protein immunohistochemistry. More than 95% of the neurons in the ipsilateral LGN survive during the first 3 days following a lesion of the visual cortex. However, in the next 4 days, massive neuronal death ensues, reducing the number of surviving neurons to approximately 33% of normal by the end of the first postoperative week. Between 2 weeks and 24 weeks postoperatively, the number of neurons present in the LGN declines very gradually from 34% to 17% of normal. Three days after a lesion of the visual cortex, the mean cross-sectional areas of ipsilateral LGN neurons are 13% smaller than normal (87%). By 1 week after the operation, surviving LGN neurons have atrophied to 66% of their normal area. Subsequently, the size of surviving neurons declines slowly to approximately 50% of normal at 24 weeks after the cortical lesion. Astrocytes in the ipsilateral LGN also react to cortical damage. At 1 day after a lesion of the visual cortex, glial fibrillary acidic protein immunoreactivity in the LGN is almost undetectable, but a distinct increase in immunoreactivity is seen at 3 days. Immunoreactivity peaks between 1 week and 2 weeks postoperatively and, thereafter, remains intense for at least 24 weeks. Thus, following a lesion of the visual cortex, the somata of neurons in the LGN remain essentially normal morphologically for about 3 days before the onset of rapid atrophy and death. Moreover, most of the neural cell death that occurs in the LGN after axotomy takes place in the last half of the first postoperative week.

Long-term protection of axotomized neurons in the dorsal lateral geniculate nucleus in the rat following a single administration of basic fibroblast growth factor or ciliary neurotrophic factor.

We have studied the long-term effects of basic fibroblast growth factor (bFGF) and ciliary neurotrophic factor (CNTF) on axotomy-induced cell death in the dorsal lateral geniculate nucleus (LGN) of adult rats. LGN neurons were axotomized by a visual cortex lesion in 31 adult rats. A gelatin sponge soaked in a solution of bFGF, CNTF, or saline (control) was placed on the surface of the lesion, and the animals were allowed to survive for 1-12 weeks. Compared with controls, no major improvement was noted in the mean cross-sectional area of surviving LGN neurons in rats treated with bFGF or CNTF at any survival time. However, treatment with either factor significantly increased the number of surviving neurons at each survival time. At 1 week, the survival of LGN neurons in rats treated with bFGF or CNTF was 136% and 131% greater, respectively, than in controls. At 12 weeks, the number of surviving LGN neurons in bFGF- and CNTF-treated rats exceeded that seen in controls by 114% and 58%, respectively. Thus, a single administration of bFGF or CNTF following axotomy reduced neuronal death for long periods of time, but could not prevent atrophy. A single treatment with bFGF or CNTF, therefore, may block the full execution of a cell death program, but cannot prevent its initiation. Alternatively, the transduction pathways for maintaining cell size and preventing cell death may not be identical, and bFGF and CNTF applied as described above may be effective in activating one pathway but not the other.

The percentage of interneurons in the dorsal lateral geniculate nucleus of the cat and observations on several variables that affect the sensitivity of horseradish peroxidase as a retrograde marker.

Ten cats ranging in age from 4 weeks postnatal to adult received large bilateral injections of horseradish peroxidase (HRP) into cortical areas 17 and 18. In one cat additional unilateral injections of HRP were made into the lateral suprasylvian visual areas (PMLS). The purpose of these injections was to label relay cells in lamina A of the dorsal lateral geniculate nucleus (LGN), in order to distinguish them from neurons that could not be labeled retrogradely. Several factors thought to influence the effectiveness of HRP as a retrograde marker were varied in an effort to label as many relay cells as possible. These factors included the (1) rate and duration of HRP injections; (2) volume and concentration of HRP injected; (3) addition of L-alpha-lysophosphatidylcholine or dimethyl sulfoxide to the injected HRP; and (4) aldehyde and buffers used for fixation. In all experiments DAB (3,3'-diaminobenzidine tetrahydrochloride) was used as the chromogen, either alone or with the addition of cobalt chloride, nickel, and cobalt salts, or cobalt-glucose oxidase. In 1-micrometer plastic sections, the influence of each of the above factors and DAB methods was determined by measuring the percentage of unlabeled neurons and the cytoplasmic HRP grain density of cells that were labeled. Our results show that approximately 22% of the neurons in lamina A of the LGN remain unlabeled following injections of HRP into areas 17 and 18 alone or combined with injections into PMLS. The percentage of unlabeled cells is similar at each of the ages that we studied and is not affected significantly by any of the factors that were varied or DAB methods that were used. Cross-sectional area measurements show that unlabeled cells tend to be among the smallest neurons in lamina A. Regardless of age, the mean size of labeled neurons was about twice that of unlabeled cells. However, we found only a weak correlation between the size of a labeled cell and the cytoplasmic density of HRP grains. Thus it is unlikely that small cell body size alone can account for the unlabeled cells in lamina A, since small neurons can be as effective in transporting HRP retrogradely as large neurons. We therefore conclude that there is a distinct population of small neurons in lamina A of the LGN that do not project to cortex. Although we cannot rule out the possibility that these cells project subcortically, we believe that it is reasonable to regard them as interneurons.

Synaptic connections between corticogeniculate axons and interneurons in the dorsal lateral geniculate nucleus of the cat.

Anatomical evidence is provided for direct synaptic connections by axons from visual cortex with interneurons in lamina A of the cat's dorsal lateral geniculate nucleus. Corticogeniculate axon terminals were labeled selectively with 3H-proline and identified by means of electron microscopic autoradiography. Interneurons in the lateral geniculate nucleus were stained with antibodies that had been raised against gamma aminobutyric acid (GABA). We found that corticogeniculate terminals synapsed with dendrites stained positively for GABA about three times as often as with unstained dendrites. Of the corticogeniculate terminals that contacted GABA-positive dendrites, 97% made synaptic connections with dendritic shafts. Only 3% synapsed with F profiles, the vesicle-filled dendritic appendages characteristic of lateral geniculate interneurons. These results suggest that the corticogeniculate pathway in the cat is directed primarily at interneurons and is organized synaptically to influence the integrated output of these cells, rather than the local interactions in which their dendritic specializations participate.

Effects of corpus callosum section on functional compensation in the posteromedial lateral suprasylvian visual area after early visual cortex damage in cats.

A visual cortex lesion made in adult cats leads to a loss of direction selectivity and a loss of response to the ipsilateral eye among cells in posteromedial lateral suprasylvian (PMLS) cortex of cats. However, a visual cortex lesion made in young cats results in normal direction selectivity and normal ocular dominance in PMLS cortex. Thus cats with an early lesion demonstrate functional compensation in PMLS cortex. The present experiment determined whether the functional compensation depends upon an intact corpus callosum. Cats received a unilateral visual cortex lesion on the day of birth (day 1) or at 8 weeks of age. When the cats were adult, the corpus callosum was sectioned and 24 hours later recordings were made in PMLS cortex ipsilateral to the visual cortex lesion. Results were compared to cats with a similar lesion and an intact corpus callosum. In cats with a lesion made on day 1, a corpus callosum section did not affect receptive-field properties or ocular dominance in PMLS cortex. Therefore, functional compensation is not dependent on input via the corpus callosum in these animals. However, in cats with a lesion made at 8 weeks. a corpus callosum section resulted in a decrease in the percentage of direction-selective cells and in the percentage of cells driven by the ipsilateral eye. Despite the decrease, the percentage of direction-selective cells still was greater than in cats with an adult unilateral visual cortex lesion. Thus, while partly dependent on callosal inputs, some functional compensation for direction selectivity remains on the basis of ipsilateral inputs.(ABSTRACT TRUNCATED AT 250 WORDS)