Peer education of pharmacists and supplying pharmacies with IDU packets to increase injection drug users' access to sterile syringes in Connecticut.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
D Katz
Publications and source records attributed to D Katz.
The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett's esophagus.
OBJECTIVE: Periodic endoscopic surveillance is generally recommended for patients with Barrett's esophagus. The optimal follow-up strategy for uncomplicated Barrett's esophagus is controversial, in part because of limited data on the rate of neoplastic progression (through the sequence of metaplasia-dysplasia-carcinoma) during endoscopic surveillance. This study aims to quantify the development of dysplasia in patients with uncomplicated Barrett's esophagus and to explore clinical risk factors associated with the development of dysplastic lesions. METHODS: We identified 102 patients with endoscopic evidence of Barrett's esophagus and the presence of specialized columnar epithelium who had received endoscopic surveillance for adenocarcinoma at our medical center between 1970 and 1994. We abstracted endoscopic and histologic data from the medical record. All specimens that showed any degree of atypia (per report) were reexamined in blinded fashion by a team of study pathologists who indicated the grade of dysplasia. Time to first diagnosis of dysplasia was plotted using Kaplan-Meier survival curves, and risk factors for development of dysplasia were assessed using Cox regression. RESULTS: During 563 patient-yr of endoscopic follow-up, three patients developed adenocarcinoma at least 4 yr after initial diagnosis (one developed adenocarcinoma of the cardia, which was incidentally detected during surveillance for Barrett's esophagus). At some point during follow-up, 19 patients developed new onset, low grade dysplasia and four developed high grade dysplasia. None of the patients who had received antireflux surgery developed dysplasia. CONCLUSION: If confirmed by larger follow-up studies, our results suggest that surveillance endoscopy can be safely deferred for at least 2 yr following an initial biopsy that is negative or indeterminate for dysplasia. Adoption of this approach would substantially reduce the cost of surveillance for adenocarcinoma. Future trials should explore the role of antireflux surgery in protecting against neoplastic transformation of Barrett's esophagus.
Adenocarcinoma↗
Xeroderma pigmentosum: spinal cord astrocytoma with 9-year survival after radiation and isotretinoin therapy.
BACKGROUND: Patients with xeroderma pigmentosum (XP) frequently develop sunlight-induced skin cancer. Infrequently, internal neoplasms may also occur. A 21-year-old patient with XP, who had many skin cancers, developed a rare internal tumour - a grade II diffuse fibrillary spinal cord astrocytoma - during a break in a therapeutic trial of isotretinoin for skin cancer prevention. Treatment of neoplasms in XP patients presents special difficulties because of their defect in DNA repair. OBJECTIVE: The study objective was to raise awareness of the cancer surveillance process in XP patients and the concerns involved in choice of therapy. METHODS: Since the spinal cord tumour was inoperable, the patient was treated with x-radiation, continued on isotretinoin treatment and was followed closely for tumour response. RESULTS: Despite sensitivity to sunlight, the patient had a normal acute response to the x-ray treatment without excessive skin reaction. Serial examinations by magnetic resonance imaging (MRI) starting 8 months after x-ray treatment was initiated, showed a marked gadolinium enhancement followed by regression. This clearing was first seen at 2 years after biopsy and persisted to at least 9 years after treatment. CONCLUSION: In contrast to the exaggerated sensitivity to UV radiation, XP patients may tolerate therapeutic doses of x-radiation. Isotretinoin treatment may have contributed to the good response of this spinal cord astrocytoma.
Adult↗
Some relationships among affection, aggression and alcohol abuse in the family setting.
Three questionnaire studies involving 101, 270, and 144 college students examined the relationship between affectionate behaviors and aggressive behaviors in the family environment as rated by the college students. Measures of affection and aggression were significantly negatively associated in nearly all analyses. Participants' ratings of parental alcohol abuse were positively associated with measures of parental aggression and negatively correlated with measures of parental affection.
Adult↗
Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease.
OBJECTIVES: Isolated reports suggest a possible association of endolymphatic sac tumors (ELSTs), which are extremely rare in the general population, with von Hippel-Lindau disease (VHL). To determine if hearing loss and ELSTs are a component of VHL, we examined prevalence, clinical presentation, and natural history of hearing loss and ELSTs in VHL. DESIGN: Brain magnetic resonance images (MRIs) from 374 patients screened for VHL were reviewed for evidence of ELSTs. The VHL patients with MRI evidence suggestive of ELSTs or a history of hearing loss, tinnitus, or vertigo underwent additional radiologic and audiologic evaluations. To further assess prevalence of hearing loss and ELST in VHL, the next 66 patients screened in the VHL clinic (49 with proven VHL, 17 at risk for VHL) received MRI and audiologic assessment. SETTING: Referral center. PARTICIPANTS: Study subjects comprised 374 persons screened for VHL, 66 consecutive patients with VHL or at risk for VHL, 4 patients with 6 ELSTs, and 13 previously reported patients with VHL and invasive tumors of the temporal bone. INTERVENTION: Magnetic resonance image and computed tomographic (CT) scan of the posterior fossa and audiologic assessment. MAIN OUTCOME MEASURES: Any ELST visible on MRI or CT and hearing loss compatible with ELST. RESULTS: Magnetic resonance imaging revealed evidence of 15 ELSTs in 13 (11%) of 121 patients with VHL, but in none of the 253 patients without evidence of VHL (P<.001). Clinical findings in these 13 patients included hearing loss (13), tinnitus (12), vertigo (8), and facial paresis (1). Mean age at onset of hearing loss was 22 years (range, 12-50 years). Hearing for pure tones was abnormal in all affected ears and in 6 of the 11 additional, allegedly unaffected ears. In 8 patients (62%), hearing loss was the first manifestation of VHL. Presence or absence of hearing loss was associated with duration of symptoms (P<.002) and with tumor size (P<.01). Further, 43 (65%) of the 66 patients from the VHL clinic had pure tone threshold abnormalities, abnormalities that occurred bilaterally in 23 (54%) of the 43 affected subjects; however, evidence is lacking for a definitive association with ELST (3 [6%] of 49 patients with proven VHL had ELST evident on MRI). CONCLUSIONS: Hearing loss and ELSTs are frequently associated with VHL syndrome and should be considered when screening individuals at risk for VHL and when monitoring patients with an established diagnosis of VHL. Many patients with VHL have hearing loss without radiographic evidence of an ELST. Whether it is caused by an ELST that is too small to be detected by MRI or is produced by some other etiology is still unknown. Audiologic evaluation and MRI should allow early detection and enhance management of hearing loss in these patients.
Age of Onset↗
Immunologic analysis of a spinal cord-biopsy specimen from a patient with human T-cell lymphotropic virus type I-associated neurologic disease.
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Biopsy↗
von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel-Lindau disease.
Central nervous system hemangioblastoma is a neoplasm with characteristic and well-described histopathological features, including proliferation of vascular and stromal cells. yet, the histogenesis of the stromal cell component and its neoplastic capacity as compared with the vascular component are still controversial. Stromal cells were selectively procured from formalin-fixed, paraffin-embedded archival tissue from a von Hippel-Lindau (VHL) disease patient with a cerebellar hemangioblastoma and studied for loss of heterozygosity (LOH) of the VHL gene locus and associated microsatellite regions. The stromal cells consistently showed LOH. Analysis of mixed stromal anti vascular areas of this tumor and four other hemangioblastomas of VHL patients showed that loss of heterozygosity was partially obscured. These preliminary results suggest that the stromal component of hemangioblastomas contains genetic alterations consistent with a neoplastic nature. Additional samples of pure stromal cells need to be analyzed to establish the prevalence of VHL gene deletion in stromal cells of capillary hemangioblastoma and, hence, its pathogenetic significance.
Cerebellar Neoplasms↗
Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells.
Intratumoral implantation of murine cells modified to produce retroviral vectors containing the herpes simplex virus-thymidine kinase (HSV-TK) gene induces regression of experimental brain tumors in rodents after ganciclovir (GCV) administration. We evaluated this approach in 15 patients with progressive growth of recurrent malignant brain tumors. Antitumor activity was detected in five of the smaller tumors (1.4 +/- 0.5 ml). In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, "bystander," mechanisms provide local antitumor activity in human tumors. However, the response of only very small tumors in which a high density of vector-producing cells had been placed suggests that techniques to improve delivery and distribution of the therapeutic gene will need to be developed if clinical utility is to be achieved with this approach.
Adult↗
Intraventricular immunotoxin therapy for leptomeningeal neoplasia.
OBJECTIVE: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms. RESULTS: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment. CONCLUSION: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.
Adult↗
Characterization of germ cell-specific expression of the orphan nuclear receptor, germ cell nuclear factor.
Nuclear receptors, such as those for androgens, estrogens, and progesterones, control many reproductive processes. Proteins with structures similar to these receptors, but for which ligands have not yet been identified, have been termed orphan nuclear receptors. One of these orphans, germ cell nuclear factor (GCNF), has been shown to be germ cell specific in the adult and, therefore, may also participate in the regulation of reproductive functions. In this paper, we examine more closely the expression patterns of GCNF in germ cells to begin to define spatio-temporal domains of its activity. In situ hybridization showed that GCNF messenger RNA (mRNA) is lacking in the testis of hypogonadal mutant mice, which lack developed spermatids, but is present in the wild-type testis. Thus, GCNF is, indeed, germ cell specific in the adult male. Quantitation of the specific in situ hybridization signal in wild-type testis reveals that GCNF mRNA is most abundant in stage VII round spermatids. Similarly, Northern analysis and specific in situ hybridization show that GCNF expression first occurs in testis of 20-day-old mice, when round spermatids first emerge. Therefore, in the male, GCNF expression occurs postmeiotically and may participate in the morphological changes of the maturing spermatids. In contrast, female expression of GCNF is shown in growing oocytes that have not completed the first meiotic division. Thus, GCNF in the female is expressed before the completion of meiosis. Finally, the nature of the two different mRNAs that hybridize to the GCNF complementary DNA was studied. Although both messages contain the DNA binding domain, only the larger message is recognized by a probe from the extreme 3' untranslated region. In situ hybridization with these differential probes demonstrates that both messages are present in growing oocytes. In addition, the coding region and portions of the 3' untranslated region of the GCNF complementary DNA are conserved in the rat.
Animals↗
Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells.
Apoptosis of the WEHI 231 immature B cell lymphoma line following membrane interaction with an antibody against the surface IgM chains (anti-IgM) is preceded by dramatic changes in Nuclear Factor-kappaB (NF-kappaB)/ Rel binding activities. An early transient increase in NF-kappaB/Rel binding is followed by a significant decrease in intensity below basal levels. Here we have explored the role of these changes in Rel-related factors in B cell apoptosis. Treatment of WEH1 231 cells with N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a protease inhibitor which prevents degradation of the inhibitor of NF-kappaB (IkappaB)-alpha, or with low doses of pyrrolidinedithiocarbamate (PDTC) selectively inhibited NF-kappaB/Rel factor binding and induced apoptosis. Bcl-XL expression protected WEHI 231 cells from apoptosis induced by these agents. Microinjection of WEHI 231 cells with either IkappaB-alpha-GST protein or a c-Rel affinity-purified antibody induced apoptosis. Ectopic c-Rel expression ablated apoptosis induced by TPCK or anti-IgM. Treatment of BALENLM 17 and A20 B lymphoma cells or normal murine splenic B lymphocytes with either TPCK or PDTC also resulted in apoptosis. These findings indicate that the drop in NF-kappaB/Rel binding following anti-IgM treatment activates apoptosis of WEHI 231 cells; furthermore, they implicate the NF-kappaB/Rel family in control of apoptosis of normal and transformed B cells.
Animals↗
Monte Carlo-based treatment planning for boron neutron capture therapy using custom designed models automatically generated from CT data.
PURPOSE: A Monte Carlo-based treatment planning code for boron neutron capture therapy (BNCT), called NCTPLAN, has been developed in support of the New England Medical Center-Massachusetts Institute of Technology program in BNCT. This code has been used to plan BNCT irradiations in an ongoing peripheral melanoma BNCT protocol. The concept and design of the code is described and illustrative applications are presented. METHODS AND MATERIALS: NCTPLAN uses thin-slice Computed Tomography (CT) image data to automatically create a heterogeneous multimaterial model of the relevant body part, which is then used as input to a Monte Carlo simulation code, MCNP, to derive distributions within the model. Results are displayed as isocontours superimposed on precisely corresponding CT images of the body part. Currently the computational slowness of the dose calculations precludes efficient treatment planning per se, but does provide the radiation oncologist with a preview of the doses that will be delivered to tumors and to various normal tissues, and permits neutron irradiation times in Megawatt-minutes (MW-min) to be calculated for specific dose prescriptions. The validation of the NCTPLAN results by experimental mixed-field dosimetry is presented. A typical application involving a cranial parallel-opposed epithermal neutron beam irradiation of a human subject with a glioblastoma multiforme is illustrated showing relative biological effectiveness-isodose (RBE) distributions in normal CNS structures and in brain tumors. Parametric curves for the MITR-II M67 epithermal neutron beam, showing the gain factors (gain factor = minimum tumor dose/maximum normal brain dose) for various combinations of boron concentrations in tumor and in normal brain, are presented. RESULTS: The NCTPLAN code provides good computational agreement with experimental measurements for all dose components along the neutron beam central axis in a head phantom. For the M67 epithermal beam the gain factor for 1, boronophenylalanine for a small midline brain tumor under typical distribution assumptions is 1.4-1.8 x . Implementation of the code under clinical conditions is demonstrated. CONCLUSION: The NCTPLAN code has been shown to be well suited to treatment-planning applications in BNCT. Comparison of computationally derived dose distributions in a phantom compared with experimental measurements demonstrates good agreement. Automatic superposition of isodose contours with corresponding CT image data provides the ability to evaluate BNCT doses to tumor and to normal structures. Calculation of gain factors suggests that for the M67 epithermal neutron beam, more advantage is gained from increasing boron concentrations in tumor than from increasing the boron tumor-to-normal brain ratio.
Boron Neutron Capture Therapy↗
Human T-cell lymphotropic virus type II-associated myelopathy: clinical and immunologic profiles.
Human T-cell lymphotropic virus type II (HTLV-II) is endemic in several ethnic tribes and among intravenous drug users in metropolitan areas. Despite the presence of HTLV-II in these various populations, the association of HTLV-II with disease is sparse and mainly limited to isolated case reports. This study is an extension of an earlier description of an HTLV-II-infected patient with neurologic disease and presents the clinical and immunologic findings of 4 patients with HTLV-II seropositivity and spastic paraparesis. The patients are of African-American origin with 3 of the patients being of Amerindian descent. All of the patients are seronegative for the human immunodeficiency virus (HIV). The patients progressed to a nonambulatory state in less than 5 years. Magnetic resonance imaging studies obtained from 3 of the patients demonstrated white matter disease in the cerebrum and spinal cord. The cerebrospinal fluid and serum contained antibodies to HTLV-II. The presence of proviral HTLV-II was confirmed by polymerase chain reaction analysis of peripheral blood lymphocytes (PBLs). A spinal cord biopsy from 1 patient demonstrated HTLV RNA within a lesion. Immunologic studies on 2 patients demonstrated that spontaneous lymphoproliferation of PBLs was present but decreased relative to HTLV-I-infected patients. The clinical and immunologic findings from these HTLV-II-infected patient resemble those found in HTLV-I-associated myelopathy/tropical spastic paraparesis.
Adult↗
The relation between brain iron and NMR relaxation times: an in vitro study.
T1 and T2 relaxation times and iron concentrations were measured in 24 specimens of gray matter from fresh human and monkey brains at magnetic fields from 0.05 to 1.5 Tesla. Three different effects were found that correlate with iron content: a T1-shortening that falls off somewhat at high fields, a T2-shortening that is field-independent and thus important at low fields, and a contribution to 1/T2 that increases linearly with field strength. This linear field dependence has been seen only in ferritin and other ferric oxyhydroxide particles. Our results are in agreement with in vivo MRI studies and are generally consistent with values for ferritin solution, except for differences such as clustering of ferritin in tissue. A cerebral cavernous hemangioma specimen showed similar T2-shortening, but with a 2.7 times larger magnitude, attributed to larger clusters of hemosiderin in macrophages. The dependence on interecho time 2 tau was measured in three brains; 1/T2 increased significantly for tau up to 32 ms, as expected from the size of the ferritin clusters. These findings support the theory that ferritin iron is the primary determinant of MRI contrast in normal gray matter.
Adult↗
Unique immunomodulating properties of dimethyl dioctadecyl ammonium bromide (DDA) in experimental viral vaccines.
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Adjuvants, Immunologic↗
Correlations between two short cognitive tests and a WISC-III short form using a sample of adolescent inpatients.
A new short form of the WISC-III was examined with a clinical adolescent sample (N = 30) and the short form estimate of WISC-III Full Scale IQ also served as the criterion for validating two brief cognitive measures, the Kaufman Functional Academic Skills Test (K-FAST) and the K-SNAP. Data supported the brevity of the WISC-III short form and the criterion-related validity of both the K-FAST and and Kaufman Short Neuropsychological Assessment Procedure (K-SNAP).
Adolescent↗
Effect of radiation on red cell membrane and intracellular oxidative defense systems.
Ionizing radiation is currently used for prevention of transfusion associated graft versus host disease (TAGVHD). As radiation damage is associated with the production of activated oxygen species, the aim of this study was to observe the immediate effect of ionizing radiation on red cell membrane and intracellular oxidative defense systems. Neonatal and iron deficiency (IDA) cells, known for their increased sensitivity to oxidative stress, were chosen and compared with normal cells. Irradiation was performed in doses of 1500 cGy, 3000 cGy and 5000 cGy. GSH and methemoglobin levels and the activity of different antioxidant enzymes, measured under optimal in vitro conditions, were preserved in all cells after irradiation. Only radiation at the highest does of 5000 cGy, caused significant potassium leakage in neonatal cells and insignificant increase in IDA cells. Thus, cells with increased sensitivity to oxidative stress are more susceptible to damage by ionizing radiation than normal cells.
Catalase↗
Multiple sclerosis: a protective or a pathogenic role for heat shock protein 60 in the central nervous system?
The stress proteins belonging to the heat shock protein 60 (hsp6O) family of molecular chaperones with known immunogenic properties are expressed at increased levels in a number of autoimmune conditions. Because previous studies from this laboratory suggested that hsp6O may be involved in the pathogenesis of the chronic multiple sclerosis (MS) plaque, we have examined autopsied central nervous system tissue from 10 cases of MS, ranging in clinical history from acute to chronic inactive. MS lesions ranged from acute, actively demyelinating and edematous, to fibrous astrogliotic and chronically demyelinated. As controls, central nervous system tissue from other neurologic diseases and nonneurologic conditions was used. Frozen, paraffin, and epoxy-embedded sections were studied immunocytochemically with the ML30 mAb to hsp6O. Acute MS lesions displayed the greatest reactivity, with particularly prominent staining of hypertrophic astrocytes, reactive macrophages, and hyperplastic oligodendrocytes. In all these cells, elevated expression occurred in the constitutive site for hsp6O (mitochondria) and within the cytosol, which is suggestive of a shift in expression. The hsp6O-reactive oligodendrocytes were structurally intact. Chronic active MS lesions also revealed the highest levels of hsp6O in hypertrophic astrocytes and oligodendrocytes. Chronic silent MS lesions displayed elevated hsp6O in hypertrophic astrocytes only while constitutive expression occurred elsewhere in the central nervous system at levels slightly higher than normal. Other neurologic disease tissue displayed expression elevated above that found in nonneurologic cases, but this was considerably less than that seen in acute MS. Of the other neurologic diseases, AIDS encephalitis revealed the greatest activity for hsp6O, with both mitochondrial and cytosolic staining of astrocytes. It is proposed that the high levels of hsp6O in hyperplastic, structurally intact oligodendrocytes in acute MS lesions may bespeak a protective mechanism, whereas hsp6O in chronic active lesions may serve a pathogenic role in the later depletion of these cells.
Acute Disease↗