A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32

We updated the clinical features of a consanguineous Arab Israeli family, in which four of seven children were affected by spastic paraplegia complicated by skin pigmentary abnormalities. A genomewide linkage screen performed for the family identified a new locus (SPG23) for this form of hereditary spastic paraplegia, in an approximately 25cM region of chromosome 1q24-q32, with a peak logarithm of odds score of 3.05.     

Concurrence of multiple sclerosis and intracranial glioma. Report of a case and review of the literature

We report a 39-year-old female patient known to have multiple sclerosis (MS), who later developed cerebral glioblastoma. The tumor was documented on the brain-magnetic resonance imaging (MRI) during the work-up for an apparent relapsing MS, and was subsequently confirmed pathologically by stereotactic biopsy and the postmortem brain examination. Our case, as well as others, re-emphasizes the need to evaluate the symptoms and brain MRI carefully, even in well-documented MS subjects. The concurrence of MS and intracranial glioma is uncommon. The possible relationship between the 2 diseases was discussed, and related literature reviewed.     

The molecular genetics of arrhythmogenic right ventricular dysplasia-cardiomyopathy

Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD or ARVC) is an inherited disorder characterized by replacement of the right ventricular myocardium by adipose and fibrous tissue and associated with sudden cardiac death. This disorder may be as prevalent as 6 in 10 000 and causes 12.5%-25% of sudden death events in the young. Nine genetic loci associated with this disease have been ascertained, and mutations in genes at 3 loci have been discovered. These genetic studies have shed light on some of the pathogenetic mechanisms. Mutations in genes encoding desmoplakin and plakoglobin suggest that altered integrity at cardiac myocyte cell-cell junctions may promote myocyte degeneration and death, with the repair process consisting of replacement of myocardium by adipose and fibrous tissue. Mutations in the gene encoding the cardiac ryanodine receptor suggest that cytoplasmic calcium overloading may lead to arrhythmias characteristic of ARVD, and perhaps also the structural changes. Many of the remaining questions concerning the pathogenesis of ARVD can be answered only by the mapping and identification of other genes associated with this disease.     

Analysis of treatment results for base of tongue cancer

OBJECTIVE: The study reported the results of treatment for base of tongue cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: This was a retrospective study of 262 patients with base of tongue cancer treated in the Departments of Otolaryngology-Head and Neck Surgery and Radiation Therapy at Washington University School of Medicine (St. Louis, MO) from July 1955 to January 1998. METHODS: The study population included previously untreated patients with biopsy-proven squamous cell carcinoma of the base of tongue who were treated with curative intent by one of five modalities and were all eligible for 5-year follow-up. The treatment modalities included local resection alone, composite resection alone, radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival (DSS) was 49.6% with death due to tumor in 50.4%. The 5-year cumulative disease-specific survival probability (CDSS) was 0.526 (Kaplan-Meier) with a mean of 7.8 years and a median of 5.6 years. Patients with early disease had significantly improved DSS compared with patients with more advanced disease (stages I and II; TN stages T1N0, T2N0, and T2N1; and T stages T1 and T2.). Patients with N0 had better DSS than patients with positive lymph nodes (P =.010). The DSS for all stages by treatment modality included local resection (70.0%), composite resection (47.6%), radiation therapy (40.4%), local resection and radiation therapy (50.0%), and composite resection with radiation therapy (51.5%). Overall and within the stages there was no significant difference in either DSS or CDSS by treatment modality. Local-regional recurrence occurred in 26% of patients, and overall salvage was 10.5%. Patients with clear resection margins did better than patients with close or involved margins (DSS and CDSS). Patients treated with radiation therapy alone had improved capacity to swallow (P =.001), speak (P =.01), and work (P =.001) compared with patients treated with the other modalities. CONCLUSIONS: Cancer of the base of tongue is a lethal disease, and its treatment results in significant disability. No treatment produced a significantly improved survival advantage. Focus on improving local-regional control might improve overall survival. All treatment modalities were associated with major treatment-related complications. Radiation alone produced significantly improved post-treatment function and quality of life compared with the other modalities. Because of the recurrence rates at the primary and neck sites and the high rates of development of distant metastasis and second primary cancers, patients should be monitored for a minimum of at least 4 years.     

Nasal ciliary studies in children with chronic respiratory tract symptoms

Ciliary abnormalities include a range of morphological dysfunctions resulting in dysmotility. These typically manifest with upper and lower respiratory symptoms later in the infancy and early childhood. The diagnosis is based on ciliary studies i.e. measurement of ciliary beat frequency (CBF). We present a series of 67 children who had nasal biopsy and ciliary studies done between 1993-2002. There were 44 boys and 23 girls of age between 1 to 17 years. In 49 (73%) cases indication of ciliary studies was chest symptoms. There were six diagnostic categories: asthma, recurrent chest infections, bronchiectasis, rhinosinusitis, dextrocardia and prematurity. Fourteen patients (20%) had dextrocardia and of these 9 had no measurable beating cilia. In the rest 5 CBF ranged 8-12.7 Hz. If the patients with dextrocardia are excluded, 5 of the 53 (10%) did not have any ciliary activity and in remaining CBF ranged 5.3-19.7 Hz. Our results showed a significant number of children with immotile cilia had associated dextrocardia. In the absence of situs inversus index of suspicion should be very high to detect these cases early. Otolaryngologists can play a key role in diagnosis because of an easy access for nasal biopsy, which is much simple than bronchial biopsies.     

Physiological validation of the concept of glycemic load in lean young adults

Dietary glycemic load, the mathematical product of the glycemic index (GI) of a food and its carbohydrate content, has been proposed as an indicator of the glucose response and insulin demand induced by a serving of food. To validate this concept in vivo, we tested the hypotheses that 1). portions of different foods with the same glycemic load produce similar glycemic responses; and 2). stepwise increases in glycemic load for a range of foods produce proportional increases in glycemia and insulinemia. In the first study, 10 healthy subjects consumed 10 different foods in random order in amounts calculated to have the same glycemic load as one slice of white bread. Capillary blood samples were taken at regular intervals over the next 2 h. The glycemic response as determined by area under the curve was not different from that of white bread for nine foods. However, lentils produced lower than predicted responses (P < 0.05). In the second study, another group of subjects was tested to determine the effects of increasing glycemic load using a balanced 5 x 5 Greco-Latin square design balanced for four variables: subject, dose, food and order. Two sets of five foods were consumed at five different glycemic loads (doses) equivalent to one, two, three, four and six slices of bread. Stepwise increases in glycemic load produced significant and predictable increases in both glycemia (P < 0.001) and insulinemia (P < 0.001). These findings support the concept of dietary glycemic load as a measure of overall glycemic response and insulin demand.     

Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors

Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) regulate colon cancer growth and metastasis. Previous studies utilizing antibodies against the VEGF receptor (DC101) or EGF receptor (C225) have demonstrated independently that these agents can inhibit tumour growth and induce apoptosis in colon cancer in in vivo and in vitro systems. We hypothesized that simultaneous blockade of the VEGF and EGF receptors would enhance the therapy of colon cancer in a mouse model of peritoneal carcinomatosis. Nude mice were given intraperitoneal injection of KM12L4 human colon cancer cells to generate peritoneal metastases. Mice were then randomized into one of four treatment groups: control, anti-VEGFR (DC101), anti-EGFR (C225), or DC101 and C225. Relative to the control group, treatment with DC101 or with DC101+C225 decreased tumour vascularity, growth, proliferation, formation of ascites and increased apoptosis of both tumour cells and endothelial cells. Although C225 therapy did not change any of the above parameters, C225 combined with DC101 led to a significant decrease in tumour vascularity and increases in tumour cell and endothelial cell apoptosis (vs the DC101 group). These findings suggest that DC101 inhibits angiogenesis, endothelial cell survival, and VEGF-mediated ascites formation in a murine model of colon cancer carcinomatosis. The addition of C225 to DC101 appears to lead to a further decrease in angiogenesis and ascites formation. Combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon peritoneal carcinomatosis.     

Three-dimensional radiotherapy of head and neck and esophageal carcinomas: a monoisocentric treatment technique to achieve improved dose distributions

The specific aim of three-dimensional conformal radiotherapy is to deliver adequate therapeutic radiation dose to the target volume while concomitantly keeping the dose to surrounding and intervening normal tissues to a minimum. The objective of this study is to examine dose distributions produced by various radiotherapy techniques used in managing head and neck tumors when the upper part of the esophagus is also involved. Treatment planning was performed with a three-dimensional (3-D) treatment planning system. Computerized tomographic (CT) scans used by this system to generate isodose distributions and dose-volume histograms were obtained directly from the CT scanner, which is connected via ethernet cabling to the 3-D planning system. These are useful clinical tools for evaluating the dose distribution to the treatment volume, clinical target volume, gross tumor volume, and certain critical organs. Using 6 and 18 MV photon beams, different configurations of standard treatment techniques for head and neck and esophageal carcinoma were studied and the resulting dose distributions were analyzed. Film validation dosimetry in solid-water phantom was performed to assess the magnitude of dose inhomogeneity at the field junction. Real-time dose measurements on patients using diode dosimetry were made and compared with computed dose values. With regard to minimizing radiation dose to surrounding structures (i.e., lung, spinal cord, etc.), the monoisocentric technique gave the best isodose distributions in terms of dose uniformity. The mini-mantle anterior-posterior/posterior-anterior (AP/PA) technique produced grossly non-uniform dose distribution with excessive hot spots. The dose measured on the patient during the treatment agrees to within +/- 5 % with the computed dose. The protocols presented in this work for simulation, immobilization and treatment planning of patients with head and neck and esophageal tumors provide the optimum dose distributions in the target volume with reduced irradiation of surrounding non-target tissues, and can be routinely implemented in a radiation oncology department. The presence of a real-time dose-measuring system plays an important role in verifying the actual delivery of radiation dose.