Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration.

The clinical evaluation of neural transplantation as a potential treatment for Huntington's disease (HD) was initiated in an attempt to replace lost neurons and improve patient outcomes. Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits. Their brains were evaluated immunohistochemically and with electron microscopy for markers of projection neurons and interneurons, inflammatory cells, abnormal huntingtin protein, and host-derived connectivity. Surviving grafts were identified bilaterally in 2 of the subjects and displayed classic striatal projection neurons and interneurons. Genetic markers of HD were not expressed within the graft. Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient's neurons, particularly the projection neuron subtype; (iv) graft survival is attenuated in the caudate in comparison to the putamen in HD; (v) glutamatergic cortical neurons project to transplanted striatal neurons; and (vi) microglial inflammatory changes in the grafts specifically target the neuronal components of the grafts. These results, when combined, raise uncertainty about this potential therapeutic approach for the treatment of HD. However, these observations provide new opportunities to investigate the underlying mechanisms involved in HD, as well as to explore additional therapeutic paradigms.

Adult central core disease. Clinical, histologic and genetic aspects: case report and review of the literature.

Central core disease (CCD) is mainly a disease of infancy and childhood and represents a member of a group of muscular disorders known as "congenital, benign (non-progressive) myopathies". It is an uncommon disease of infancy and early childhood, and presentation is rare in adulthood. The disease is mainly familial with an autosomal-dominant pattern of inheritance, yet sporadic cases can occur. The diagnosis is based on a muscle biopsy, which documents unique morphological abnormalities of focal loss of oxidative enzyme in type I muscular fibers. The basis for this loss of such activities is represented by a near-total absence of mitochondria and sarcoplasmic reticulum in the cores. We describe a 58-year-old man diagnosed with CCD, who is one of the oldest individuals reported with CCD diagnosed by a muscle biopsy. The clinical, pathological and genetic features of this rare entity are discussed herein.

Improved survival mediated by Corynebacterium parvum following allogeneic bone marrow transplantation in rabbits.

The effect of Corynebacterium parvum on survival was studied in aplastic rabbits transplanted with allogeneic bone marrow cells. Twenty four hours after receiving 1200 rad of total body irradiation, NZW males were reconstituted from unrelated R females using bone marrow combined with spleen cells or with marrow alone. The effects of treating donor, or both donor and recipient, with C parvum were contrasted. Rabbits in Group I were infused with a mixture of bone marrow and spleen cells. In control aminals (Group Ia) none of the 14 animals survived to 40 days. Similarly, there were no survivors among 17 animals in group Ib where only the donors were pretreated with C. parvum. When both donor and recipient received this agent (Group Ic) three of the 13 animals (23%) survived beyond 40 days. Animals in Group II were infused with marrow cells alone. Of the controls (Group IIa), 3 out of 24 animals (12.5%) survived to 40 days; pretreatment of the donor with C. parvum (Group IIb) resulted in survival of 8 of the 18 animals (44%); when both donor and recipient received this agent (Group IIc), 16 of 26 animals (62%) survived beyond 40 days. Both the incidence and the severity of histologically demonstrable graft-versus-host disease was markedly reduced in the surviving animals. These observations demonstrate a significant effect of parenteral C. parvum on the prolongation of survival in the irradiated rabbit following transplantation with allogeneic bone marrow cells, which is related to reduction in GVHD.

Cloning and expression in Escherichia coli of a recA-like gene from Bacteroides fragilis.

The recombinant plasmid pHG100, containing a 5.2-kb DNA fragment from Bacteroides fragilis, complemented defects in homologous recombination, DNA repair and prophage induction to various levels in an Escherichia coli recA mutant strain. There was no DNA homology between the cloned B. fragilis recA-like gene and E. coli chromosomal DNA. pHG100 produced two proteins with Mr of approx. 39,000 and 37,000 which cross-reacted with antibodies raised against E. coli RecA protein. The production of these proteins was not increased after UV induction. The cloned B. fragilis recA-like gene product did not enhance the production of native but defective E. coli RecA protein after UV irradiation.

Insulin-like growth factor-binding protein-1 is correlated with low density lipoprotein cholesterol in normal subjects.

Insulin-like growth factor-I (IGF-I) has been inversely associated with low-density lipoprotein (LDL) cholesterol in normal women with slightly elevated cholesterol levels and hypothyroid women. More than 95% of IGF-I circulates bound to binding proteins (IGFBPs); of these IGFBP-1 is of particular interest as it is inversely regulated by insulin and is thought to inhibit the action of IGF-I and IGF-II. We examined the relationship between IGFBP-1 and LDL cholesterol in 41 healthy adult subjects. LDL cholesterol correlated with the body mass index (r = 0.40, P < 0.01), sex (r = 0.51, P < 0.001) and IGFBP-1 levels (r = 0.36, P < 0.02). LDL cholesterol did not correlate with age (r = 0.25, P = not significant) or IGF-I (r = 0.06, P = not significant). Upon multivariate regression analysis, sex, body mass index and IGFBP-1 were all independent predictors of LDL cholesterol (all P < 0.05). Elevated IGFBP-1 levels have been associated with an inhibition of serum IGF-I bioactivity in children with insulin-dependent diabetes. IGFBP-1 also appears to inhibit IGF-I hexose-stimulated uptake. IGFBP-1 may also be inhibiting the effect of IGFs on the cellular metabolism of LDL cholesterol.

Efficacy of gadoteridol for contrast-enhanced magnetic resonance imaging in children.

RATIONALE AND OBJECTIVES: This study assesses the efficacy of gadoteridol for contrast-enhanced magnetic resonance imaging (MRI) in children. METHODS: Patients were examined by MRI before and after receiving 0.10 mmol/kg gadoteridol. Blinded and unblinded readers analyzed brain and spine MRI studies from a multicenter clinical trial involving 101 patients at 11 sites. Ninety-two cases (76 brain, 16 spine) were evaluated by unblinded investigators, and 91 cases (76 brain, 15 spine) were evaluated by three neuroradiologists unaffiliated with any investigational site and blinded to clinical information. RESULTS: Unblinded readers noted enhancement of brain pathology in 70% of cases versus 50% to 67% among blinded readers. Unblinded readers determined that additional diagnostic information was available after contrast in 82% of brain studies (average, 64% for blinded readers) and would have changed patient diagnoses in 48% of these studies (average, 46% for blinded readers). In spine cases, enhancement of pathology was noted in 38% (unblinded) and 33% to 40% (blinded). Additional diagnostic information was available after contrast in 63% of spine studies (unblinded), or an average of 58% (blinded), and patient diagnoses would have changed in 20% (unblinded), or an average of 59% (blinded). CONCLUSIONS: Gadoteridol is suitable for enhanced MRI detection, localization, and characterization of central nervous system pathology in children.

Efficacy of gadoteridol for magnetic resonance imaging of extracranial head and neck pathology.

RATIONALE AND OBJECTIVES: This study evaluated the efficacy of gadoteridol in patients with extracranial head and neck pathology. METHODS: One hundred twenty-two magnetic resonance imaging (MRI) cases from a multicenter safety and efficacy trial of gadoteridol in patients with suspected head and neck pathology were randomly assigned for evaluation to one of two blinded neuroradiologists. RESULTS: Enhancement of pathology after gadoteridol injection was noted in 96 cases (78.7%) and provided additional diagnostic information in 57 cases (46.7%). Improved lesion visualization was noted in 37 (64.9%) of these 57 cases; an increase in the number of lesions seen was noted in 4 (7.0%) of 57 cases. Blinded readers determined that additional diagnostic information provided by gadoteridol would have resulted in a change in diagnosis in 20 (35.1%, or 16.4% of total population) of 57 patients. CONCLUSION: These results demonstrate that gadoteridol is an efficacious agent for enhanced MRI of head and neck pathology.

Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.

RATIONALE AND OBJECTIVES: To determine the safety and pharmacokinetics of gadobenate dimeglumine in a group of subjects with moderate or severe renal impairment. METHODS: The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter trial. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ content by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood concentration/time data were analyzed nonparametrically and parametrically using the software program WinNonlin VI.1. RESULTS: Mean (SD) values for Gd3+ area under the curve, blood clearance, steady-state volume of distribution, renal clearance, and creatinine clearance for the moderate group were 862 (392) micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events occurred. Mean values for Gd3+ recovery in urine and feces for moderate and severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearance of Gd3+. CONCLUSIONS: Although mean blood clearance and renal clearance values progressively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the standard dose used for MRI purposes, there appears to be no need for dose reduction in this population.

Antineuronal nuclei immunohistochemical staining patterns in childhood ependymomas.

NeuN, the mouse-derived monoclonal antibody to the reportedly neuron-specific nuclear protein, has been observed to react with many different types of normal, postmitotic neurons throughout the central and peripheral nervous systems. We retrospectively examined 23 surgical specimens (collected from 20 patients) originally diagnosed at our institution between 1983 and 1999 as ependymoma (9), myxopapillary ependymoma (1), anaplastic/malignant ependymoma (10), and primitive neuroectodermal tumor with ependymal differentiation (3). The ependymomas included lesions from the spine (3), cerebrum (5), and posterior fossa (15). Representative formalin-fixed, paraffin-embedded sections from each tumor were subjected to immunohistochemical staining with antibody against NeuN (Chemicon International, Inc, Temecula, CA). Five astrocytomas, four primitive neuroectodermal tumors, and normal cerebral cortex and ependyma from autopsy brains of premature newborns, term infants, and older children served as controls. Thirteen ependymal tumors had positive nuclear staining ranging from rare tumor cells to numerous groups of cells; of these, 9 were anaplastic ependymomas and had the most staining. These studies suggest that some ependymomas arise from a pluripotential neuroglial cell.

A blood pressure independent index of aortic distensibility.

A non-invasive Doppler ultrasound technique for the assessment of aortic compliance based on the in vivo measurement of pulse wave velocity along the thoraco-abdominal aortic pathway is described. An approach for correcting for the effect of blood pressure on aortic compliance is considered. The derivation of an index of distensibility, Cp, which is independent of blood pressure is provided and applied to data collected from 58 normal, healthy volunteers. Medical disorders such as atherosclerosis, diabetes mellitus and familial hypercholesterolaemia have all been shown to affect arterial distensibility. We suggest that the clinical measurement of Cp may be a useful, non-invasive tool for assessing such patients' susceptibility to atheromatous arterial disease as well as for monitoring their response to therapy.

Aortic distensibility in post-menopausal women receiving Tibolone.

Both oestrogen and androgens have been shown to affect the structural composition and biophysical properties of the arterial wall in vitro. A non-invasive Doppler ultrasound technique, based on the measurement of pulse wave velocity along the thoraco-abdominal aortic pathway, was used to assess aortic compliance C in vivo in 49 normotensive, normal, healthy post-menopausal female subjects. 23 of the women had been receiving Tibolone, a synthetic steroid structurally related to norethisterone, for at least 3 years. Since C varies with non-chronic changes in blood pressure, an index of intrinsic aortic distensibility, Cp, normally independent of blood pressure, was also calculated. No significant difference was found between the control group and those subjects receiving Tibolone for age, body mass index, systolic blood pressure, diastolic blood pressure, C or Cp. As one would expect the control group Cp values did not show a significant relationship with blood pressure (r = -0.1, not significant). However, in the Tibolone group some dependence of Cp values on pressure still remained (r = -0.58, p < 0.004), suggesting that oral administration of Tibolone had altered the dynamic relationship between structural and functional biophysical properties of the aortic wall in vivo.

Pseudotumor cerebri: a review.

Pseudotumor cerebri (PTC) is a syndrome seen more frequently in young, obese women defined by increased intracranial pressure without obstruction of the ventricular system. Normal neurodiagnostic studies, normal cerebrospinal fluid (CSF) contents, papilledema in one or both eyes, and normal mental status should also be recognized. Although the disorder has been associated with drugs, endocrinopathies, compromised nutritional status and other disease states, no underlying disorder is uniformly present.

Intracerebral mesenchymal chondrosarcoma.

The current case report deals with a 14-year-old girl with an intracerebral mesenchymal chondrosarcoma which has been recognized in two males and two females varying from 25 to 59 years of age. Three of the five patients had an associated malignant glioma. The present girl died eight years after her initial neurologic deficits and never received any definitive treatment for her deep seated neoplasm. These unique sarcomas may be confused with vascular lesions and have not been found to spread through the neuraxis. This unusual primary intracerebral mesenchymal chondrosarcoma appears to represent a field phenomenon with cartilaginous differentiation of glial and mesenchymal elements in the central nervous system.

Intracranial diffuse axonal injury at autopsy.

An illustrative case of diffuse axonal injury (DAI) emphasizes features that help to separate focal outer head trauma owing to blows and/or falls from angular acceleration head injuries associated with diffuse inner brain lesions. In the past, explaining significant neurological deficits and death as the result of diffuse closed head trauma received from high-speed automobile accidents has been difficult as well as confusing. The long-term consequences from such diffuse inner cerebral trauma are still poorly defined. Head injuries sustained in automobile accidents have been associated with diffuse brain damage characterized by axonal injury at the moment of impact. The reported victim of a motor vehicle accident showed post-mortem findings for both inner cerebral trauma and focal outer cerebral damage. The diffuse degeneration of cerebral white matter is associated with sagittal and lateral acceleration with centroaxial trauma and has a different pathogenesis from outer focal head trauma, typified by subdural hematomas and coup injuries. Unlike outer cerebral injury, over 50 percent of victims with diffuse axonal injury die within two weeks. These individuals characteristically have no lucid interval and remain unconscious, vegetative, or severely disabled until death. Compared to head trauma victims without diffuse axonal injury, there is a lower incidence of skull fractures, subdural hemorrhages, or other intracranial mass effect as well as outer brain contusions. Primary brainstem injuries often demonstrated at autopsy are seen in the reported victim. Diffuse axonal injury is produced by various angles of acceleration with prolonged acceleration/deceleration usually accompanying traffic accidents. Less severe diffuse axonal injury causes concussion.

Hypertension and vascular dementia.

Postmortem surveys on patients treated for chronic hypertension often fail to demonstrate significant vessel changes. Nevertheless, hypertensive alterations in the brain can include infarcts and hemorrhages. Autopsies in a primary care hospital have shown that hypertension can affect arteries, arterioles, and capillaries in various patterns and degrees in the brain. These vascular lesions may be associated with large and small infarcts and hemorrhages in isolated or diffuse patterns. Widespread cerebral edema can occur with rapidly progressive hypertension. Atherosclerosis, arterial and arteriolar fibrinoid necrosis, and micro-aneurysms may be observed. Chronic hypertensive encephalopathy causes vascular dementia and can be associated with subcortical arterial and arteriolar leukoencephalopathy, leukoaraiosis and/or Binswanger's disease. Epidemiologic evaluations based on complete autopsy studies need to be correlated with compliance of therapy, appropriate diagnosis of hypertension, and its long-term effects on the nervous system. Although persistent poorly controlled hypertension is known to damage the brain both acutely and chronically, the effects of intermittent hypertension remain to be defined.

Invasive polymycotic pneumonia in an uncontrolled diabetic.

We describe the clinical course of a patient with invasive polymycotic pneumonia due to Rhizopus arrhizus and Candida albicans. Both organisms were recovered from antemortem sputum cultures, and their clinical significance was confirmed by histologic examination of the lungs at autopsy. Circumstances leading to polymycotic infection are discussed, with special attention given to polymycotic infections involving Zygomycetes.

Prevalence and severity of periodontitis in a high fluoride area in South Africa.

The prevalence of periodontal disease is widespread throughout the world. Its severity varies considerably and the factors responsible for this variation are not known. Although the effect of fluoride on the reduction of dental caries is well established, its effect on chronic inflammatory periodontal disease is obscure. In this investigation, the prevalence and severity of periodontitis in 71 adults residing in a high fluoride area (2-3 ppm) was studied. In spite of large amounts of plaque and the prevalence of severe gingivitis in these individuals, there was little evidence of periodontal destruction (mean probing depth = 2.5 mm; mean loss of attachment = 1.02 mm). The possible reasons for the resistance of this population to = 1.02 mm). The possible reasons for the resistance of this population to periodontitis are discussed.

The spectrum of pediatric injuries after a bomb blast.

The spectrum of pediatric injuries seen after a bomb blast is poorly documented. The pathophysiology of blast injuries differ significantly from other forms of trauma and typically result in large numbers of distinctly patterned injuries. On April 19, 1995, a truck bomb was detonated directly adjacent to the Alfred P. Murrah Federal Building in Oklahoma City, Oklahoma. A total of 816 adults and children were injured or killed as a direct result of the blast. Twenty infants and children were seated by the window of the second floor day care center at the time of the explosion. The injuries incurred by all children involved in the blast were studied. Nineteen children, 16 of whom were in the day care center, died as a direct result of the blast. The injury patterns among the 19 dead children included a 90% (17 of 19) incidence of skull fractures, 15 of those with cerebral evisceration (skull capping); 37% with abdominal or thoracic injuries; 31% amputations; 47% arm fractures, 26% leg fractures; 21% burns; and 100% with extensive cutaneous contusions, avulsions, and lacerations. Forty-seven children sustained nonfatal injuries with only seven children requiring hospitalization. The injuries sustained by the seven hospitalized children included two open, depressed skull fractures, with partially extruded brain, two closed head injuries, three arm fractures, one leg fracture, one arterial injury, one splenic injury, five tympanic membrane perforations, three corneal abrasions, and four burn cases (1 > 40% body surface area [BSA]). After a bomb blast, pediatric patients sustain a high incidence of cranial injuries. Fractures and traumatic amputations are common. Intraabdominal and thoracic injuries occur frequently in the deceased but infrequently in survivors.

Aspiration biopsy findings in amyloid tumor of the cervical vertebra. A case report.

BACKGROUND: The differential diagnosis of destructive lytic lesions of the spine includes amyloid tumors. The diagnosis of amyloid tumor with fine needle aspiration biopsy (FNA) is challenging. Previous reports of FNA of osseous amyloid tumors have detailed the cytologic appearance of amyloid along with lymphocytes, plasma cells and histiocytes, occasionally multinucleate or forming granulomatous lesions. CASE: An 84-year-old man presented with neck pain. Radiologic studies showed a destructive, lytic lesion of C-6, with a large, soft tissue mass. FNA yielded many acellular smears containing abundant amyloid that was confirmed with special stains of corresponding tissue cores and subsequent surgical biopsies. CONCLUSION: Osseous amyloid tumors are destructive, lytic lesions that mimic other processes. Amyloid can be distinguished from other substances in FNA samples and amyloid tumor identified, even when amyloid is present without typical cellular components.

Invasive Haemophilus influenzae type B disease.

Invasive bacterial disease due to Haemophilus influenzae is a cause of sudden death in children. It must be considered by medical examiners when a child dies with a fulminant course and nonspecific symptoms. Three fatal cases are presented in children 7 weeks to 15 months of age. Two had meningitis and petechiae or purpura. All three had bilateral adrenal hemorrhage and a rapidly fatal course. The potential for rapid and accurate diagnosis of H. influenzae infection is widely available due to latex agglutination technique against bacterial capsular wall antigens. Diagnosis is critical because of its public-health implications. Up to 50% of cases may be acquired in day-care settings. Chemoprophylaxis is recommended for household and day care contacts. With the recent introduction of Haemophilus b conjugate vaccines for routine administration to infants beginning at 2 months of age, a change in the epidemiology of the disease is anticipated.