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Biomedical subjects

H Kennedy

Publications and source records attributed to H Kennedy.

At least 19 recordsLinked to original sources
PubMed2002

Association of plasma phospholipid transfer protein activity with IDL and buoyant LDL: impact of gender and adiposity.

Current data suggest that phospholipid transfer protein (PLTP) has multiple metabolic functions, however, its physiological significance in humans remains to be clarified. To provide further insight into the role of PLTP in lipoprotein metabolism, plasma PLTP activity was measured, and lipoproteins were analyzed in 134 non-diabetic individuals on a controlled diet. Insulin sensitivity index (Si) and body fat composition were also determined. Plasma PLTP activity was comparable between men (n=56) and women (n=78). However, in women but not in men, plasma PLTP activity was positively correlated with cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, and apolipoprotein (apo) B (r=0.38-0.45, P< or =0.001), and with body mass index (BMI), subcutaneous and intra-abdominal fat (SCF, IAF) (r=0.27-0.29, P<0.02). Among the different apo B-containing lipoproteins (LpB) in women, PLTP was most highly correlated with intermediate density lipoproteins (IDL) and buoyant LDL (r=0.45-0.46, P<0.001). The correlation with IDL was significant only in women with BMI < or =27.5 kg/m(2) (n=56). In men with BMI < or =27.5 kg/m(2) (n=35), PLTP activity was significantly correlated with buoyant LDL (r=0.40, P<0.02) and high density lipoprotein (HDL) (r=0.43, P<0.01). These data provide evidence for a role of PLTP in LpB metabolism, particularly IDL and buoyant LDL. They also suggest that gender and obesity-related factors can modulate the impact of PLTP on LpB.

Adipose Tissue↗
PubMed2001

Plasma phospholipid transfer protein activity in patients with low HDL and cardiovascular disease treated with simvastatin and niacin.

Plasma phospholipid transfer protein (PLTP) is an important modulator of high-density lipoprotein (HDL) metabolism, regulating its particle size, composition, and mass. In patients with low HDL and cardiovascular disease (CVD), plasma PLTP activity is positively correlated with the concentration of HDL particles containing apo A-I but not apo A-II (Lp(A-1)). We recently completed a study to determine the effect of simvastatin and niacin (S-N) therapy on disease progression/regression in these patients, and found that this therapy selectively increased Lp(A-I). To determine if PLTP was also increased with this drug therapy, we measured the PLTP activity in the plasma of 30 of these patients obtained at baseline and after 12 months of therapy, and compared the changes to a similar group of 31 patients who received placebo for the drugs. No significant increase in PLTP activity was observed in either group of patients. However, changes in apo A-I and A-II between these two time points were correlated with the corresponding change in PLTP activity. The correlation coefficients were r=0.57 (P=0.001) and r=0.43 (P=0.02) for apo A-I, and r=0.54 (P=0.002) and r=0.41 (P=0.02) for apo A-II in the placebo and S-N group, respectively. At baseline, PLTP activity correlated positively with the percent of plasma apo A-I associated with Lp(A-I) (r=0.38, P=0.04) and the amounts of apo A-I in these particles (r=0.43, P=0.02). These relationships persisted in patients who took placebo for 12 months (r=0.46, P=0.009 and r=0.37, P=0.04, respectively), but was attenuated in those treated with S-N. These data indicate that S-N-induced increase in Lp(A-I) was PLTP-independent. It also confirms our previous observation that an interrelationship exists between PLTP and apo-specific HDL particle subclasses in CVD patients with low HDL, and that this relationship is altered by drug intervention.

Adult↗
PubMed2001

Cell-cycle kinetics of neocortical precursors are influenced by embryonic thalamic axons.

Thalamic afferents are known to exert a control over the differentiation of cortical areas at late stages of development. Here, we show that thalamic afferents also influence early stages of corticogenesis at the level of the ventricular zone. Using an in vitro approach, we show that embryonic day 14 mouse thalamic axons release a diffusable factor that promotes the proliferation of cortical precursors over a restricted developmental window. The thalamic mitogenic effect on cortical precursors (1) shortens the total cell-cycle duration via a reduction of the G(1) phase; (2) facilitates the G(1)/S transition leading to an increase in proliferative divisions; (3) is significantly reduced by antibodies directed against bFGF; and (4) influences the proliferation of both glial and neuronal precursors and does not preclude the action of signals that induce differentiation in these two lineages. We have related these in vitro findings to the in vivo condition: the organotypic culture of cortical explants in which anatomical thalamocortical innervation is preserved shows significantly increased proliferation rates compared with cortical explants devoid of subcortical afferents. These results are in line with a number of studies at subcortical levels showing the control of neurogenesis via afferent fibers in both vertebrates and invertebrates. Specifically, they indicate the mechanisms whereby embryonic thalamic afferents contribute to the known early regionalization of the ventricular zone, which plays a major role in the specification of neocortical areas.

Animals↗
PubMed2001

Pre- and post-mitotic events contribute to the progressive acquisition of area-specific connectional fate in the neocortex.

The adult primary motor cortex (area 6) is characterized by a stronger projection to the spinal cord than the primary somatosensory cortex (area 3). Here we have explored the progressive and regressive phenomena that determine these areal differences in the number of corticospinal neurons (CSNs). CSNs were birthdated with [(3)H]thymidine and subsequently retrogradely labeled from the spinal cord. The time window of CSN production is identical in both areas. The probability that a cohort of neuroblasts project to the spinal cord is indicated by the percentage of [(3)H]thymidine-positive neurons that can be back-labeled from the spinal cord. In the neonate this fate index is significantly higher in area 6 compared with area 3, indicating that early regionalization of cell fate contributes to areal differences in CSN number. In neonatal reeler mice, an increase in CSN number was accompanied by an increased fate index, showing that the integrity of the post-mitotic environment is required for the specification of the appropriate number of neurons expressing a given connectional phenotype. Postnatal development in reeler and normal is characterized by an area-specific elimination of CSN axons, which reduces areal differences in CSN number. These results show a progressive acquisition of CSN fate in the neocortex and indicate that both early regionalization and late environmental signals contribute to determining areal differences of connectional phenotype.

Animals↗
PubMed2001

Implanon: when is the ideal time to insert?

The single rod implant was introduced to the UK in October 1999. This case illustrates a problem encountered with the timing of its insertion and highlights a possible note of caution.

Adult↗
PubMed2000

Binocular competition does not regulate retinogeniculate arbor size in fetal monkey.

Binocular interactions play a prominent role in shaping the axonal arbors of geniculocortical fibers and the arbors of Y cells in the retinogeniculate pathway of the fetal cat. Fiber interactions between the two eyes have also been suggested to regulate the formation of retinal projections to the dorsal lateral geniculate nucleus (dlgn) of the fetal monkey, but whether this reflects structural refinements of retinal arbors has not been established. To address this issue, we quantified the morphologic properties of individual fibers in two macaque monkeys at embryonic day (E) 110 and E121 that had an eye removed at E69 and E61, respectively. Fibers were labeled by DiI crystals into the fixed optic tract and were visualized by confocal microscopy. Three measurements were made: the number of branch points within the axon terminal arbor, the total arborization length, and the incidence of axonal side branches on the preterminal axon within the confines of the geniculate. There were no significant differences with respect to these parameters between the prenatal enucleates and normal monkeys of comparable age. This was the case for retinal fibers innervating the magnocellular and the parvocellular segments of the dlgn. The arbors stemming from the remaining eye were widely distributed in the dlgn, with some terminating in territories normally innervated by the other (enucleated) eye. These results lend support to the hypothesis that the expanded projection from the remaining eye to the lateral geniculate nucleus of the prenatally enucleated monkey is due to the maintenance of a contingent of retinal fibers normally eliminated by ganglion cell death.

Animals↗
PubMed2000

Laminar distribution of neurons in extrastriate areas projecting to visual areas V1 and V4 correlates with the hierarchical rank and indicates the operation of a distance rule.

The directionality of corticocortical projections is classified as feedforward (going from a lower to higher hierarchical levels), feedback (interconnecting descending levels), and lateral (interconnecting equivalent levels). Directionality is determined by the combined criteria of the laminar patterns of the axon terminals as well as the cells of origins and has been used to construct models of the visual system, which reveals a strict hierarchical organization (Felleman and Van Essen, 1991; Hilgetag et al., 1996a). However, these models are indeterminate partly because we have no indication of the distance separating adjacent levels. Here we have attempted to determine a graded parameter describing the anatomical relationship of interconnected areas. We have investigated whether the precise percentage of labeled supragranular layer neurons (SLN%) in each afferent area after injection in either visual areas V1 or V4 determines its hierarchical position in the model. This shows that pathway directionality in the Felleman and Van Essen model is characterized by a range of SLN% values. The one exception is the projection of the frontal eye field to area V4, which resembles a feedforward projection. Individual areal differences in SLN% values are highly significant, and the number of hierarchical steps separating a target area from a source area is found to be tightly correlated to SLN%. The present results show that the hierarchical rank of each afferent area is reliably indicated by SLN%, and therefore this constitutes a graded parameter that is related to hierarchical distance.

Animals↗
PubMed2000

Non-uniformity of neocortex: areal heterogeneity of NADPH-diaphorase reactive neurons in adult macaque monkeys.

We have examined the distribution of cortical neurons in adult monkey cortex which stain for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), an enzyme which is involved in the synthesis of nitric oxide. In order to compare distributions across areas we employed a cortical unit defined as the radial column, which refers to the volume of cortex below 1 mm(2) of cortical surface. Numbers of labeled neurons per radial column generate areal density measurements either for the full thickness of the cortex or for individual layers. Measurements were made in six cortical regions (areas V1, V2, STS, auditory cortex, area 4 and area 6). NADPH-d stains nonpyramidal neurons which can be divided into two major groups. Type 1 neurons have large soma diameters, stain densely for NADPH-d and show few morphological variations both within and across areas. Type 2 neurons have small somata and short processes, and can be subdivided on the basis of soma size into dense and light staining categories. Both subcategories of type 2 neurons show significant areal variations in size. In each cortical area the majority of type 1 neurons are located in the white matter. Areal densities of type 1 neurons are minimal in areas V1 and V2, and twice as dense in the frontal cortex. Pairwise comparisons of areal densities among the six areas examined show that in a radial column throughout the full thickness of cortex, areas differ significantly from each other in 12/15 comparisons. Consideration of individual layers shows significant differences in 13/15 comparisons. Type 2 neurons are exclusively located in the cortical gray matter, and in all areas are considerably more numerous than type 1 neurons. Area V1 is unique it that it has up to three times the areal density found in any other cortical area. With reference to published laminar cell density counts our results show that the percentage of labeled NADPH-d neurons in individual layers of area V1 are significantly higher than in the other areas. The laminar distributions of type 1 and type 2 neurons show that each area has a unique profile of NADPH-d expression. The modular or columnar organization of the cortex, also referred to as the radial column hypothesis, is important for understanding both the development and function of the cortex. The present results show that radial columns in individual cortical areas possess distinctive patterns of NADPH-d expression. This important degree of areal heterogeneity of NADPH-d neurons has far reaching implications for both the development and functions of neocortical areas.

Animals↗
PubMed2000

Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a).

BACKGROUND: As part of the NIH/National Heart, Lung and Blood Institute Contract for the Standardization of Lipoprotein(a) [Lp(a)] Measurements, a study was performed in collaboration with the IFCC Working Group for the Standardization of Lp(a) Assays. The aims of the study, performed with the participation of 16 manufacturers and 6 research laboratories, were to evaluate the IFCC proposed reference material (PRM) for its ability to transfer an accuracy-based value to the immunoassay calibrators and to assess concordance in results among different methods. METHODS: Two different purified Lp(a) preparations with protein mass concentrations determined by amino acid analysis were used to calibrate the reference method. A Lp(a) value of 107 nmol/L was assigned to PRM. After uniformity of calibration was demonstrated in the 22 evaluated systems, Lp(a) was measured on 30 fresh-frozen sera covering a wide range of Lp(a) values and apolipoprotein(a) [apo(a)] sizes. RESULTS: The among-laboratory CVs for these samples (6-31%) were, in general, higher than those obtained for PRM (2.8%) and the quality-control samples (14%, 12%, and 9%, respectively), reflecting the broad range of apo(a) sizes in the 30 samples and the sensitivity of most methods to apo(a) size heterogeneity. Thus, although all of the assays were uniformly calibrated through the use of PRM, no uniformity in results was achieved for the isoform-sensitive methods. CONCLUSIONS: Linear regression analyses indicated that to various degrees, apo(a) size heterogeneity affects the outcome of the immunochemical methods used to measure Lp(a). We have also shown that the inaccuracy of Lp(a) values determined by methods sensitive to apo(a) size significantly affects the assessment of individual risk status for coronary artery disease.

Calibration↗
PubMed1999

Prenatal development of retinogeniculate axons in the macaque monkey during segregation of binocular inputs.

In the fetal monkey the projections from the two eyes are initially completely intermingled within the dorsal lateral geniculate nucleus (DLGN) before separating into eye-specific layers (). To assess the cellular basis of this developmental process, we examined the morphological properties of individual retinogeniculate axons in prenatal monkeys of known gestational ages. The period studied spanned the time from when binocular overlap has been reported to be maximum, circa embryonic (E) day 77 through E112, when the segregation process is already largely completed in the caudal portion of the nucleus. Retinogeniculate fibers were labeled by making small deposits of DiI crystals into the fixed optic tract. After adequate time was allowed for diffusion of the tracer, fibers were visualized by confocal microscopy, and morphometric measures were made from photomontages. This revealed that retinogeniculate fibers in the embryonic monkey undergo continuous growth and elaboration during binocular overlap and subsequent segregation. Importantly, very few side-branches were found along the preterminal axon throughout the developmental period studied. Thus, restructuring of retinogeniculate fibers does not underlie the formation of eye-restricted projections in the primate. Rather, the results support the hypothesis that binocular segregation in the embryonic monkey is caused by the loss of retinal fibers that initially innervate inappropriate territories ().

Animals↗
PubMed1999

Introduction of the human PLTP transgene suppresses the atherogenic diet-induced increase in plasma phospholipid transfer activity in C57BL/6 mice.

The human plasma phospholipid transfer protein (PLTP) has been shown to facilitate the transfer of phospholipids between lipoproteins and convert high-density lipoproteins into larger and smaller particles in vitro. To explore the lipid transport function in vivo, transgenic C57BL/6 mice that express the human PLTP gene, driven by its natural promoter, were generated. Little difference in PLTP activity and lipoprotein lipids was observed between transgenic mice and non-transgenic control mice fed the chow diet. In response to an atherogenic high-fat, high-cholesterol, cholic acid containing diet, the PLTP activity increased significantly with time in control mice (62% in males and 34% in females after the high-fat diet for 18 weeks). In contrast, the PLTP activity did not change appreciably in the transgenic mice fed the atherogenic diet. Thus, the introduction of the human transgene suppressed the diet-induced increase in plasma PLTP activity, as evidenced by a decrease in PLTP mRNA in a variety of tissues. High-density lipoprotein levels decreased in mice fed the atherogenic diet, but there was a proportionally greater decrease in transgenic animals than in controls. After 18 weeks on the atherogenic diet, the transgenic animals had high-density lipoprotein-cholesterol and PLTP activity approximately one-half of that of control animals. Non-denaturing gradient gel electrophoresis of plasma indicated that the atherogenic diet decreased the high-density lipoprotein size distribution in control mice. However, high-density lipoprotein particle size distribution of the transgenic mice was shifted to smaller particles compared with control animals (P < 0.001). These findings suggest that PLTP activity can modulate the effects of an atherogenic diet on high-density lipoproteins.

Animals↗
PubMed1999

Fish intake, independent of apo(a) size, accounts for lower plasma lipoprotein(a) levels in Bantu fishermen of Tanzania: The Lugalawa Study.

Plasma lipoprotein(a) [Lp(a)] levels are largely genetically determined by sequences linked to the gene encoding apolipoprotein(a) [apo(a)], the distinct protein component of Lp(a). Apo(a) is highly polymorphic in length due to variation in the numbers of a sequence encoding the apo(a) kringle 4 domain, and plasma levels of Lp(a) are inversely correlated with apo(a) size. In 2 racially homogeneous Bantu populations from Tanzania differing in their dietary habits, we found that median plasma levels of Lp(a) were 48% lower in those living on a fish diet than in those living on a vegetarian diet. Considering the relationship between apo(a) size and Lp(a) plasma concentration, we have extensively evaluated apo(a) isoform distribution in the 2 populations to determine the impact of apo(a) size in the determination of Lp(a) values. The majority of individuals (82% of the fishermen and 80% of the vegetarians) had 2 expressed apo(a) alleles. Additionally, the fishermen had a high frequency of large apo(a) isoforms, whereas a higher frequency of small isoforms was found in the vegetarians. When subjects from the 2 groups were matched for apo(a) phenotype, the median Lp(a) value was 40% lower in Bantus on the fish diet than in those on the vegetarian diet. A significant inverse relationship was also found between plasma n-3 polyunsaturated fatty acids and Lp(a) levels (r=-0.24, P=0.01). The results of this study are consistent with the concept that a diet rich in n-3 polyunsaturated fatty acids, and not genetic differences, is responsible for the lower plasma levels of Lp(a) in the fish-eating Bantus and strongly suggest that a sustained fish-based diet is able to lower plasma levels of Lp(a).

Adult↗
PubMed1999

Relationship between phospholipid transfer protein activity and HDL level and size among inbred mouse strains.

Because of the paucity of data on phospholipid transfer protein (PLTP) activity and lipoprotein phospholipid in mouse strains, plasma PLTP activity (PLTA), plasma phospholipid and cholesterol, HDL phospholipid and cholesterol, and HDL size distribution were determined in 15 inbred mouse strains. The 15 inbred mouse strains differed in their relatedness to one another and consisted of six largely unrelated groups: Castaneus, Swiss, C57BL, AKR, DBA, and NZB. Lipid and PLTA analyses were performed on plasma pools from male and female mice that had fasted for 4 h prior to blood draw. Among the representative unrelated strains fed the chow diet, there was a highly significant relationship between PLTA and plasma phospholipid (r(s) = 0.727, P < 0.01), HDL phospholipid (r(s) = 0.762, P < 0.01), HDL cholesterol (r(s) = 0.699, P < 0.02), percentage of large HDL particles (r(s) = 0.699, P < 0.02), and HDL peak size (r(s) = 0.776, P < 0.01). Similar results were obtained among these strains fed a high fat, high cholesterol diet. PLTA increased in all strains fed the high fat diet (chix = 94%, range 6 to 221%). Strain SM having relatively low PLTA and HDL was crossed with strain NZB having high PLTA and HDL. The F1 progeny from this cross were backcrossed to strain SM and 41 male backcross progeny collected. Among these individual backcrossed animals, PLTA was highly correlated with plasma phospholipid (r(s) = 0.508, P = 0.001), HDL phospholipid (r(s) = 0.566, P < 0.001), HDL cholesterol (r(s) = 0.532, P < 0.001), and percentage of large HDL particles (r(s) = 0.446, P = 0.020). Therefore, we conclude that PLTP is a determinant of HDL level and size in mice.-Albers, J. J., W. Pitman, G. Wolfbauer, M. C. Cheung, H. Kennedy, A-Y. Tu, S. M. Marcovina, and B. Paigen. Relationship between phospholipid transfer protein activity and HDL level and size among inbred mouse strains.

Animals↗
PubMed1998

Neurogenesis and commitment of corticospinal neurons in reeler.

In the homozygous (but not the heterozygous) reeler mutant, disruption of neuron migration leads to a major perturbation of the cortical environment that in turn could modify (1) the specification of neuronal fate and (2) the proliferation dynamics of cortical precursors. To investigate these issues, tritiated thymidine injections during cortical neurogenesis were coupled with postnatal injections of a retrograde tracer in the spinal cord to accurately measure the neurogenesis of corticospinal neurons in the heterozygous and homozygous mutant. The homozygous reeler shows (1) strict conservation of area-specific timetables of corticospinal neuron generation; (2) neurons with the appropriate birthdates show an enhanced probability of projecting to the spinal cord; (3) during early stages of corticogenesis, there is a reduced rate of neuron production followed at later stages by an increased rate of neuron production; and (4) these changes in the rate of neuron production were shown to be at least partially attributable to changes in the proportions of differentiative divisions. Taken together, our results show that in the developing cortex, the neurogenesis and specification of a given neuronal phenotype are partially controlled by the postmigratory compartment. On the other hand, neither areal identity nor the chronology of production of layer-specific neuronal phenotype seems to depend on the integrity of the cellular environment.

Afferent Pathways↗