Abraham Hirshberg

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Background Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells. Methods and Findings A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patients peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors. Conclusions This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

Are the polarization colors of Picrosirius red-stained collagen determined only by the diameter of the fibers?

SummaryPolarization colors of various purified collagens were studied in fibers of similar thickness. Three different soluble collagens of type I, insoluble collagen type I, lathyritic collagen type I, two p-N-collagens type I, pepsin extract collagen type II, two soluble collagens type III, p-N-collagen type III, and soluble collagen type V were submitted to a routine histopathologic procedure of fixation, preparation of 5-μm-thick sections, staining with Picrosirius red and examination under crossed polars. Polarization colors were determined for thin fibers (0.8 μm or less) and thick fibers, (1.6–2.4 μm). Most thin fibers of collagens and p-N-collagens showed green to yellowish-green polarization collors with no marked differences between the various samples. Thick fibers of all p-N-collagens, lathyritic and normal 0.15 M NaCl-soluble collagens showed green to greenish-yellow polarization colors, while in all other collagens, polarization colors of longer wavelengths (from yellowish-orange to red) were observed. These data suggested that fiber thickness was not the only factor involved in determining the polarization colors of Picrosirius red-stained collagens. Tightly packed and presumably, better aligned collagen molecules showed polarization colors of longer wavelengths. Thus, packing of collagen molecules and not only fiber thickness plays a role in the pattern of polarization colors of Picrosirius red-stained collagens.

Experimental tongue cancer in desalivated rats

A group of 39 rats underwent excision of the submandibular and sublingual glands and ligation of the parotid ducts through the midventral incision of the neck, while the control group (41 rats) underwent a sham operation. All rats were administered 4NQO in a final concentration of 0.001% in drinking water. At 7, 14, 22 and 28 weeks after administering 4NQO, both groups of rats were killed and their tongues dissected, inspected and then fixed in 10% buffered formalin for histopathological examination. Clinical examination during the first 14 weeks revealed that rats in both groups looked healthy and no differences in body weight were noticed. Afterwards, the average weight gain of the desalivated rats was lower than in the control group (P < 0.01). The number of macroscopic oral lesions increased with time in both groups. However, in the desalivated rats, the first identifiable lesions were seen as early as week 7, whereas in the control group macroscopic lesions were seen only after 22 weeks. Histological examination revealed more affected rats in the desalivated group in the first 14 weeks after administering the carcinogen; lesions showed more severe pathological changes including two cases with evidence of squamous cell carcinoma. The differences between the desalivated groups and control decreased after 22 weeks with almost no differences at the end of the experiment.

Pneumomediastinum and subcutaneous emphysema following surgical extraction of mandibular third molars: Three case reports

Three cases of subcutaneous emphysema following surgical extraction of lower third molars are presented. In two of the cases, pneumomediastinum developed. The direct cause of these complications is the combination of the use of an air turbine dental handpiece and the flap design. The propagation of the emphysema and means for its prevention are discussed.

Advanced early and late atrioventricular block in acute inferior wall myocardial infarction

Seventy-six patients with acute inferior acute myocardial infarction (AMI) and advanced atrioventricular (AV) block are described. According to pre-established ECG criteria and time of appearance of the advanced AV block, patients were divided into two groups. The early block group consisted of 31 patients who developed advanced AV block during the hyperacute ECG stage of AMI. Advanced AV block in these patients was characterized by early appearance, short duration, third-degree type block, poor response to atropine, and increased need for pacemaker therapy. The late block group consisted of 45 patients who developed advanced AV block during subsequent ECG stages of AMI. Advanced AV block in these patients was characterized by late appearance, longer duration, second-degree type block, positive response to atropine, and diminished need for pacemaker therapy. Morbidity and mortality also differed between both groups. Patients with early block had more syncope (32% vs 2%, p less than 0.0001), more left heart failure (36 vs 7%, p less than 0.005), and more cardiogenic shock (39% vs 2%, p less than 0.001) than patients with late block. The mortality rate in the early block group was high (23%) and similar to that reported in the literature, whereas the mortality rate in the late block group was low (7%, p less than 0.05) and similar to the mortality rate reported for acute inferior AMI without advanced AV block. These data identify a subgroup of patients with acute inferior AMI and advanced AV block, which accounts for the high mortality rate reported in this group of patients.

Identification of RNA editing sites in the SNP database

The relationship between human inherited genomic variations and phenotypic differences has been the focus of much research effort in recent years. These studies benefit from millions of single-nucleotide polymorphism (SNP) records available in public databases, such as dbSNP. The importance of identifying false dbSNP records increases with the growing role played by SNPs in linkage analysis for disease traits. In particular, the emerging understanding of the abundance of DNA and RNA editing calls for a careful distinction between inherited SNPs and somatic DNA and RNA modifications. In order to demonstrate that some of the SNP database records are actually somatic modification, we focus on one type of these modifications, namely A-to-I RNA editing, and present evidence for hundreds of dbSNP records that are actually editing sites. We provide a list of 102 RNA editing sites previously annotated in dbSNP database as SNPs, and experimentally validate seven of these. Interestingly, we show how dbSNP can serve as a starting point to look for new editing sites. Our results, for this particular type of RNA editing, demonstrate the need for a careful analysis of SNP databases in light of the increasing recognition of the significance of somatic sequence modifications.

Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma

The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma (AKT) viral oncogene pathway is involved in regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes associated with the PI3K/AKT pathway including PI3K, AKT, RAS and PTEN, are infrequently found within head and neck squamous cell carcinoma and more specifically are rarely reported in oral squamous cell carcinoma (OSCC) cases. We aimed to investigate the frequency of mutations in AKT1, PTEN, PIK3CA, and RAS (K-RAS, N-RAS, H-RAS) genes in 37 cases of oral squamous cell carcinoma (OSCC). Mutational analysis of PTEN, RAS, PIK3CA and AKT genes was performed using chip-based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and by direct sequencing. The only gene mutated in our series was the PIK3CA. Missense mutations of the PIK3CA gene were found in 4 of our cases (10.8%); no correlation has been found with oral location, stage and survival. The absence of mutations in AKT1, PTEN, and RAS genes in the present study is in accordance with previous studies confirming that these genes are rarely mutated in OSCC. Our data confirm that PIK3CA is important to OSCC tumorigenesis and can contribute to oncogene activation of the PIK3CA/AKT pathway in OSCC. The knowledge of the PIK3CAs involvement in OSCC is important because a specific kinase inhibitor could be considered as a future therapeutic option for OSCC patients with PIK3CA mutations.

Metastatic tumors to postextraction sites

Review of the literature revealed 55 cases where tooth extraction preceded the discovery of metastases. The lung and breast were the most common sources of the metastasis, and the mandibular premolar area was the most common site. A soft tissue mass extruding from a recent extraction wound, and accompanied by pain, were the main symptoms in most patients. The mean time from discovery of the metastasis to death was 3.8 months. Tooth extraction appears to serve as a promoting factor in the metastatic process. A case of metastatic transitional cell carcinoma of the urinary bladder involving the area of a recently extracted mandibular third molar is reported.

Temporomandibular joint involvement in malignant external otitis.

OBJECTIVE The purpose of this study was to present 6 patients with malignant external otitis (MEO) that resulted in temporomandibular joint (TMJ) involvement and to discuss the incidence, clinical presentation, and treatment modalities. STUDY DESIGN All patients diagnosed with MEO between 1994 and 2002 were reviewed for cases in which the TMJ was invaded by the infectious process. Only patients in whom TMJ involvement was documented radiographically and in whom the clinical course was well documented were included in this study. RESULTS MEO was diagnosed in 42 patients over an 8-year period; TMJ involvement was recorded in 6 patients (14%). The medical history revealed controlled type 2 diabetes mellitus in 4 of the 6 patients. All patients reported early ear symptoms, mainly otalgia and otorrhea. Local signs included an ear canal filled with granulation material, edematous overlying skin, and sensitivity to palpation. Cultures taken from the external ear were positive for either Pseudomonas aeruginosa, Staphylococcus epidermidis, Aspergillus, or Proteus mirabilis. TMJ symptoms developed between 1 and 5 months after admission and included painful periauricular swelling and trismus. In 3 patients, healing was uneventful; 3 also died of the disease. CONCLUSIONS TMJ involvement in MEO is associated with a resistant disease process, often with several recurrences. Prolonged administration of antibiotics is the treatment of choice. Surgical debridement of the TMJ is necessary for the positive identification of the pathogenic organism, in cases of abscess formation, or when osteomyelitic bone destruction of the condyle and glenoid fossa develop.

Histomorphologic and morphometric changes in minor salivary glands of the rat tongue during 4-nitroquinoline-1-oxide-induced carcinogenesis

4-Nitroqinoline-1-Oxide (4NQO)-induced tongue carcinogenesis in rats is considered to be a preferred model for study of oral squamous cell carcinoma. Aim of study was to investigate histomorphologic and morphometric 4NQO-induced changes in tongue minor salivary glands. Histopathological examinations of serous and mucous acini and ducts of tongue salivary glands of 26 Wistar-derived rats were performed after 14 (T(1)), 22 (T(2)) and 28 (T(3)) weeks of 0.001% 4NQO administration in drinking water and compared with nine controls. Histomorphological findings were recorded as normal/abnormal acini and as normal/dysplastic ducts. Morphometrical results were expressed as volume fraction (Vv%) of each of the components. Morphometric and histomorphologic changes in the salivary glands were evident only at T(3) and they included a significant (P=0.008) decrease in the Vv of the serous acini compared with the control group accompanied by abnormal acini (Vv=18%). In contrast, mucous acini and ducts did not demonstrate significant changes. In one case (3.8%), dysplastic ducts were found adjacent to islands of invasive squamous cell carcinoma of tongue mucosa origin. The change in saliva composition expected after considerable damage of the serous glands could create a microenvironment that makes entrapment of the carcinogen easier and prolongs exposure of tongue epithelium. Furthermore, the dysplastic changes in the ducts can serve as a reservoir of carcinoma cells. These observations should be considered in human patients diagnosed with oral dysplasia or carcinoma, especially involving the tongue and floor of mouth.