Biomedical subjects

Christa L Hladik

Publications and source records attributed to Christa L Hladik.

10 recordsLinked to original sources

PubMed2005

The t(14;18) in diffuse large B-cell lymphoma: correlation with germinal center-associated markers and clinical features.

The clinical and biologic relevance of the t(14;18) and features of germinal center (GC) differentiation in diffuse large B-cell lymphoma (DLBCL) remain controversial. The authors examined the association of t(14;18) with GC-associated markers and clinical features in 44 de novo DLBCLs (22 nodal and 22 primary extranodal). CD10, bcl-2, and bcl-6 were expressed in 50%, 62%, and 54% of cases respectively. There were no significant differences in expression of these markers between nodal and extranodal cases. Coexpression of CD10 and bcl-6 was seen in 12 of 41 cases, and was more frequent in nodal than extranodal DLBCL (9 of 21 vs. 3 of 20; P = 0.05). A CD10+/bcl-6+ phenotype was not significantly associated with bcl-2 expression, stage, complete remission rate, or survival. The t(14;18) was found in 7 of 44 (16%) cases (6 nodal, 1 extranodal; P = 0.09). It was associated with a CD10+/bcl-6+ phenotype (5 of 7 vs. 7 of 27; P = 0.015) and a trend toward more frequent bcl-6 expression (6 of 7 vs. 15 of 34; P = 0.09), but no association with bcl-2 expression, CD10, clinical stage, complete remission, or survival. Among nodal or high-stage (III-IV) DLBCL, cases with the t(14;18) showed a trend toward decreased survival (P = 0.12).

Adolescent↗

PubMed2005

Differences in ERK activation in squamous mucosa in patients who have gastroesophageal reflux disease with and without Barrett's esophagus.

OBJECTIVES: In some patients with gastroesophageal reflux disease (GERD), the reflux-damaged esophageal squamous epithelium heals through the process of intestinal metaplasia (resulting in Barrett's esophagus) rather than through the regeneration of more squamous cells. We hypothesized that squamous epithelium in Barrett's esophagus might have abnormalities in activation of the extracellular-regulated kinases 1 and 2 (ERK1/2) signaling pathway that may facilitate esophageal repair through metaplasia in response to acid-induced injury. METHODS: Endoscopic biopsies were taken from distal esophageal squamous mucosa in patients who had GERD with and without Barrett's esophagus and in controls, before and after esophageal perfusion with 0.1 N HCl acid. Basal ERK1/2 phosphorylation, acid-induced ERK1/2 activity and phosphorylation, and localization of phosphorylated ERK1/2 were determined using immunoblotting, Western blotting, and immunohistochemistry. RESULTS: Compared to patients with Barrett's esophagus, patients with GERD exhibited significantly lower baseline levels of phosphorylated ERK1/2 expression (35 +/- 4%vs 90 +/- 21% control, p= 0.01) Acid exposure significantly increased ERK1/2 activity (346.6 +/- 51.90 to 446.8 +/- 62.44 RIU, p= 0.02) and phosphorylation (3.55 +/- 1.26 to 4.49 +/- 1.25 [ratio phospho/total ERK], p= 0.01) in the squamous mucosa of GERD patients, but not in those with Barrett's esophagus or in controls. CONCLUSIONS: Between patients with Barrett's esophagus and patients with uncomplicated GERD, there are significant differences in baseline levels and in acid-induced activation of ERK1/2 in esophageal squamous epithelium. To our knowledge, this is the first description of a molecular, phenotypic feature that distinguishes the esophageal squamous mucosa of GERD patients with and without Barrett's esophagus.

Adult↗

PubMed2004

Alpha-synuclein expression in the developing human brain.

Alpha (alpha)-synuclein is a presynaptic protein, abnormal expression of which has been associated with neurodegenerative and neoplastic diseases. It is abundant in the developing vertebrate central nervous system (CNS), but less is known about its developmental expression in the human CNS. Immunohistochemical expression of alpha-synuclein was studied in 39 fetal, perinatal, pediatric, and adolescent brains. Perikaryal expression of alpha-synuclein is observed as early as 11-wk gestation in the cortical plate. Several discrete neuronal groups in the hippocampus, basal ganglia, and brain stem express perikaryal alpha-synuclein by 20-wk gestation, persisting through the first few years of life. In the cerebellum, alpha-synuclein is present by 21-wk gestation and persists into adult life as a coarse granular neuropil reaction product in the internal granular layer, and as a diffuse neuropil "blush" in the molecular layer. The germinal matrix, glia, endothelial cells, external granular layer, Pukinje cells, and dentate neurons are consistently negative for alpha-synuclein. We conclude that alpha-synuclein is expressed very early in human gestation, and that its distribution and temporal sequence of expression varies in discrete neuronal groups. Perikaryal alpha-synuclein starts disappearing from the neuronal cytosol in early childhood, and only the neuropil retains immunoreactivity into adulthood. The reappearance of alpha-synuclein in the adult neuronal cytosol in certain disease processes may represent reemergence of cues from an earlier developmental stage as part of a stress response.

Adolescent↗

PubMed2004

Beta-amyloid precursor protein immunohistochemistry in the evaluation of pediatric traumatic optic nerve injury.

OBJECTIVE: The pathologic markers of nonaccidental injury (NAI) of the central nervous system (CNS) of infants and young children include subdural, subarachnoid, and retinal hemorrhages. Immunohistochemical staining for beta-amyloid precursor protein (betaAPP) has been used to investigate traumatic axonal injury of the brain, brain stem, and spinal cord injuries, and has potential as an additional indicator of traumatic head injury. A single study has reported that betaAPP immunostaining of the optic nerve in CNS NAI reveals axonal damage. The purpose of our study was to explore further the utility of betaAPP immunostaining of optic nerves for the detection of traumatic axonal injury. METHODS: We used hematoxylin-eosin and betaAPP immunostaining to evaluate the eyes and optic nerves in 18 cases of CNS nonaccidental blunt force head injury, 4 cases of homicidal blunt force abdominal injury (BFAI), 1 homicidal suffocation, 1 case of sudden infant death syndrome, 1 near-drowning, 1 overlay (clinical history: "found under sleeping mother in bed"), 1 motor vehicle accident, and 6 natural deaths in children < or =5 years of age. RESULTS: Evaluation of the cases of CNS NAI revealed 17 of 18 (94%) with subdural hemorrhage; 15 of 18 (83%), subarachnoid hemorrhage; 17 of 18 (94%), retinal hemorrhage; 16 of 18 (88%), perioptic nerve hemorrhage; and 6 of 18 (33%), optic nerve betaAPP immunoreactive axonal swellings. The only nontraumatic case that demonstrated betaAPP immunoreactive axonal swellings was the near-drowning. No cases of BFAI, suffocation, overlay, or natural deaths revealed any retinal or perioptic nerve hemorrhage or significant optic nerve betaAPP immunoreactivity. Global hypoxic-ischemic injury was present in 21 cases, of which 19 had evidence of brain swelling, and 7 demonstrated betaAPP immunoreactive axonal swellings. CONCLUSIONS: These findings confirm the presence of optic nerve axonal injury in some cases of fatal pediatric CNS NAI.

Amyloid beta-Protein Precursor↗

PubMed2004

Percutaneous translumbar spinal cord compression injury in dogs from an angioplasty balloon: MR and histopathologic changes with balloon sizes and compression times.

BACKGROUND AND PURPOSE: Our previous model of spinal cord injury (SCI) included six dogs undergoing 30-minute compression with a balloon in the subarachnoid space. We determined whether various balloon sizes and compression times creates a gradation of injuries. METHODS: In 17 dogs (including our original six), angioplasty balloons 2, 4, or 7 mm in diameter (2 cm long) were inflated at T6 for 30, 120, or 240 minutes. T1- and T2-weighted, gadolinium-enhanced, and short-tau inversion recovery (STIR) MR images were obtained at 1.5 T. Spinal canal occlusion (SCO) was measured as balloon area-spinal cord area. Hematoxylin-eosin and beta amyloid precursor protein staining were performed to demonstrate hemorrhage and axonal injury, respectively. Injuries were scored as mild, moderate, or severe. Trends were assessed with one-way analysis of variance. RESULTS: SCO was 12.5-20% for 2-mm balloons, 28-56% for 4 mm, and 62-82% for 7 mm. No abnormalities were seen with SCO <30%. T1- and T2-weighted images had the poorest diagnostic performance; STIR images were best for predicting hemorrhage and axonal injury. Hemorrhage was demonstrated more frequently than was axonal injury. SCO (P < .0001) and hemorrhage (P = .002) significantly increased with balloon size. Longer inflation times tended to increase injuries for a given size, but differences were not significant. CONCLUSION: Compression injuries depended on the level of SCO. The compression times tested had less effect than the degree of compression. The value of 1.5-T MR imaging varied with the sequence and improved with contrast enhancement. STIR images showed SCIs not otherwise detected.

Angioplasty, Balloon↗

PubMed2003

Constitutive and regulated expression of the mouse Dinb (Polkappa) gene encoding DNA polymerase kappa.

A recently discovered group of novel polymerases are characterized by significantly reduced fidelity of DNA synthesis in vitro. This feature is consistent with the relaxed fidelity required for the replicative bypass of various types of base damage that frequently block high fidelity replicative polymerases. The present studies demonstrate that the specialized DNA polymerase kappa (polkappa) is uniquely and preferentially expressed in the adrenal cortex and testis of the mouse, as well as in a variety of other tissues. The adrenal cortex is the sole site of detectable expression of the Polkappa gene in mouse embryos. This adrenal expression pattern is consistent with a requirement for polkappa for the replicative bypass of DNA base damage generated during steroid biosynthesis. The expression pattern of polkappa in the testis is specific for particular stages of spermatogenesis and is distinct from the expression pattern of several other low fidelity DNA polymerases that are also expressed during spermatogenesis. The mouse (but not the human) Polkappa gene is primarily regulated by the p53 gene and is upregulated in response to exposure to various DNA-damaging agents in a p53-dependent manner.

Adrenal Cortex↗

PubMed2003

Beta-amyloid precursor protein staining of nonaccidental central nervous system injury in pediatric autopsies.

Immunohistochemical staining for beta-amyloid precursor protein (betaAPP) is a well-established marker of traumatic axonal injury in adults. Recent studies have used similar techniques to evaluate nonaccidental central nervous system injury (NAI) in infants and young children. In this prospective study, we report the results of betaAPP immunohistochemistry on the brain and spinal cord in 28 pediatric cases of NAI. BetaAPP-immunoreactive axons were present in 27/28 cases. Vascular axonal injury (VAI) due to brain swelling and secondary vascular compromise was the most common pattern of betaAPP immunoreactivity and was detected in 22 of 28 cases. Traumatic axonal injury was detected in 19/28 cases, although only eight of these cases showed brainstem staining, thus fulfilling the criteria for the diagnosis of diffuse traumatic axonal injury (dTAI). TAI and VAI were both present in 16/28 cases. Isolated TAI and VAI occurred in three and five cases, respectively. All children with isolated VAI were <18 months of age. An additional finding highlighted by betaAPP immunostaining was a penumbra of axonal injury adjacent to focal lesions, such as lacerations. We conclude that betaAPP immunohistochemistry aids in documenting trauma in nonaccidental central nervous system injury in infants and young children and that VAI is a common finding.

Age Factors↗

PubMed2003

Beta-amyloid precursor protein staining in nonhomicidal pediatric medicolegal autopsies.

Immunohistochemical staining for beta-amyloid precursor protein (betaAPP) has been validated as a marker for axonal injury in adults surviving > or = 2 hours after white matter damage. The significance of betaAPP staining in pediatric brains and spinal cords is not as well established. We evaluated the white matter immunoreactivity for betaAPP from a variety of pediatric medicolegal autopsies: natural disease (non-Sudden Infant Death Syndrome [SIDS]), SIDS, motor vehicle accidents, drowning, near-drowning, overlay, carbon monoxide toxicity, miscellaneous trauma, and mechanical asphyxia. The cases of carbon monoxide toxicity, motor vehicle accidents (death at scene), drowning (with resuscitation), and a natural (non-SIDS) death had no significant white matter staining. The traumatic deaths with a significant survival interval, a variety of natural deaths, the near-drowning case, and surprisingly, all SIDS had detectable betaAPP white matter immunostaining. These results demonstrate that features other than traumatic axonal injury, such as metabolic insults and hypoxic-ischemic injury secondary to vascular compromise, must contribute to betaAPP immunostaining. In addition, we describe a variety of betaAPP-immunoreactive structures not previously reported in the pediatric population. This study illustrates that betaAPP immunostaining enhances detection of a variety of white matter changes, and provides a basis for interpretation of these results.

Amyloid beta-Protein Precursor↗

PubMed2003

Percutaneous translumbar spinal cord compression injury in a dog model that uses angioplasty balloons: MR imaging and histopathologic findings.

BACKGROUND AND PURPOSE: Previous animal models for spinal cord injury required laminectomy and exposure of the spinal cord to create direct trauma, compromising imaging by both surgical artifact and the nature of the production of the injury. Our purpose was to study a model that uses percutaneous intraspinal navigation with an angioplasty balloon, providing a controlled degree of spinal cord compression and allowing improved MR imaging of spinal cord injury. METHODS: Nine mongrel dogs were studied. MR images were obtained of six dogs after technique development in three dogs. Angioplasty balloons measuring 7 or 4 mm in diameter and 2 cm in length were placed in the midthoracic subarachnoid space. Imaging was performed by using a 1.5-T MR imaging unit before and after balloon inflation. The balloon was inflated within 5 seconds and deflated after 30 minutes. T1- and T2-weighted and contrast-enhanced images were acquired. Spinal cords were submitted for pathologic examination. RESULTS: All four animals with 7-mm balloons experienced hemorrhage, and three had axonal injury revealed by histopathologic examination. One of two animals with 4-mm balloons experienced no injury, and one had axonal injury without hemorrhage. Regional parenchymal enhancement was seen in two of the animals with 7-mm balloons. CONCLUSION: This percutaneous spinal cord injury model results in a graduating degree of injury. It differs from previous techniques by avoiding surgical exposure and the associated artifacts, yet it offers histopathologic findings similar to those of human spinal cord injury. The canine spinal cord is amenable to MR imaging with clinical imaging units. Further evaluations with various durations of compression and various balloon sizes are warranted.

Angioplasty, Balloon↗

PubMed2002

DNA polymerase kappa deficiency does not affect somatic hypermutation in mice.

Somatic hypermutation (SH) in B cells undergoing T cell-dependent immune responses generates high-affinity antibodies that provide protective immunity. Most current models of SH postulate the introduction of a nick into the DNA and subsequent replication-independent, error-prone short-patch synthesis by one or more DNA polymerases. The Pol kappa (DinB1) gene encodes a specialized mammalian DNA polymerase called DNA polymerase kappa (pol kappa), a member of the recently discovered Y family of DNA polymerases. The mouse PolK gene is expressed at high levels in the seminiferous tubules of the testis and in the adrenal cortex, and at lower levels in most other cells of the body including B lymphocytes. In vitro studies showed that pol kappa can act as an error-prone polymerase, although they failed to ascribe a clear function to this enzyme. The ability of pol kappa to generate mutations when extending primers on undamaged DNA templates identifies this enzyme as a potential candidate for the introduction of nucleotide changes in the immunoglobulin (Ig) genes during the process of SH. Here we show that pol kappa-deficient mice are viable, fertile and able to mount a normal immune response to the antigen (4-hydroxy-3-nitrophenyl)acetyl-chicken gamma-globulin (NP-GC). They also mutate their Ig genes normally. However, pol kappa-deficient embryonic fibroblasts are abnormally sensitive to killing following exposure to ultraviolet (UV) radiation, suggesting a role of pol kappa in translesion DNA synthesis.

Animals↗