Subacute combined degeneration of the spinal cord: MR findings

The authors present the initial and follow-up MR findings in a patient with subacute combined degeneration of the spinal cord, a complication of vitamin B12 deficiency, and a rare cause of demyelination of the dorsal and lateral columns of the spinal cord. Initial study showed high intensity in the dorsal columns of the cervical and thoracic spinal cord on T2-weighted image. Five months after treatment, the abnormal signal intensity was noted to have decreased.     

Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.     

Comparison of estrogen receptor DNA binding in untreated and acquired antiestrogen-resistant human breast tumors

Preliminary studies have suggested that measuring the ability of immunoreactive 67-kDa estrogen receptor (ER) to bind DNA and form in vitro complexes with its cognate estrogen response element (ERE) might serve to identify breast tumors most likely to respond to antiestrogens like tamoxifen. Data from two different surveys of untreated primary breast tumors confirmed that only 67% (74 of 111) of ER-positive tumors express a receptor capable of forming ER-ERE complexes by gel-shift assay, with tumors of lower ER content having significantly reduced ER DNA-binding frequency (56%) relative to those of higher ER content (82%; P = 0.007). In contrast to these untreated tumors, a panel of 41 receptor-positive breast tumors excised after acquiring clinical resistance to tamoxifen during either primary (n = 26) or adjuvant therapy (n = 15) showed a significantly greater ER DNA-binding frequency, with nearly 90% capable of forming ER-ERE complexes (P < 0.02). To assess experimentally whether ER DNA-binding function is altered during the development of antiestrogen resistance, nude mouse MCF-7 tumor xenografts were analyzed before and after the acquisition of in vivo resistance to either tamoxifen or a pure steroidal antiestrogen, ICI 182,780. Tamoxifen-resistant MCF-7 tumors retained full expression of 67-kDa DNA-binding ER, and despite a markedly reduced ER content in the ICI 182,780-treated tumors, the expressed ER in these antiestrogen-resistant tumors exhibited full ability to form ER-ERE complexes. These findings indicate that breast tumors with acquired antiestrogen resistance continue to express ER of normal size and DNA-binding ability and suggest that the failure of antiestrogens to arrest tumor growth during emergence of clinical resistance results from an altered gene-regulatory mechanism(s) other than ER-ERE complex formation.     

Age differences in stable carbon and nitrogen isotope ratios in a population of prehistoric maize horticulturists

Stable carbon isotope ratios in prehistoric human bone collagen have been used extensively to document the introduction and intensification of maize horticulture in notheastern North America. Most previous studies are based on small samples of adults who are assumed to characterize the diet of the population. In this study, all 29 individuals buried within an Ontario Iroquoian village site dated A.D. 1530-1580 were analysed for stable isotopes of carbon and nitrogen. Age distribution of the sample ranges from preterm to elderly. Significant negative correlations between age and delta 13C, and age and delta 15N values were found. High delta 13C values in infants and young children (delta 13C = -6.8 to -12.3) suggest a weaning diet high in maize. High delta 15N values in infants relative to adults suggest a trophic level effect during breast-feeding which has been reported in a modern sample by Tuross et al. (Am. J. Phys. Anthropol., 1993). In addition to the isotopic evidence for extremely high carbohydrate (maize) intake, the MacPherson sample includes two juveniles aged 3-4 years, exhibiting circular caries. No other cases of this condition are known in the extensively studied southern Ontario skeletal collections. Together the evidence from dentition and stable carbon isotopes indicates a very high carbohydrate diet in subadults. Circular caries result from developmental stress during enamel formation with subsequent caries formation in areas of thinner enamel. These findings are relevant to studies of infant and early childhood morbidity and mortality among prehistoric maize horticulturists.     

Profile hidden Markov models

The recent literature on profile hidden Markov model (profile HMM) methods and software is reviewed. Profile HMMs turn a multiple sequence alignment into a position-specific scoring system suitable for searching databases for remotely homologous sequences. Profile HMM analyses complement standard pairwise comparison methods for large-scale sequence analysis. Several software implementations and two large libraries of profile HMMs of common protein domains are available. HMM methods performed comparably to threading methods in the CASP2 structure prediction exercise.     

Clinical picture, diagnosis and therapy of acromegaly patients in Eastern and Western Germany

Acromegaly, a chronic disease characterized by an excessive secretion of growth hormone (GH), is not commonly diagnosed timely enough. Therefore, investigations have been conducted through standardized questionnaires concerning the path to diagnosis, clinical data, therapy, and the patient care of 46 acromegalic patients. The acquired information has been compared in the former Eastern and Western German states. The mean duration of disease before diagnosis was estimated to be 6.1 +/- 5.3 years in the area surrounding Erlangen and 9.3 +/- 7.3 years in the Leipzig and Dresden areas. Despite current trends, a significant difference could not be established regarding the age in which the first symptoms are noted, time of diagnosis, and the delay between the two points in time General practitioners have diagnosed about 35 percent of the occurrences of acromegaly, 15 percent of the cases were accidentally found and about as many were discovered in hospitals. 11 percent of the occurrences were diagnosed by neurologists and another 11 percent by internists. The remaining cases were established by eye specialists. ENT departments, orthopedic specialists or gynaecologists. The most frequent symptoms are increased acral growth, coarse facial features and excessive sweating. For 91 percent of the acromegaly patients, surgery was voted as the therapy of choice. Acromegalic patients have learned the most about their disease through personal contact with doctors, especially endocrine specialists. Many patients are not informed enough about the possible complications of their disease. Through gathered data, it has been concluded that in Eastern and Western Germany the disease has not been identified soon enough. Interdisciplinary teamwork among doctors is a basis for early diagnosis, as well as better patient awareness and education.     

Daytime sleepiness: when is it normal? When to refer?

Most disorders that cause daytime sleepiness can and should be identified and treated. Physicians should recognize that excessive daytime sleepiness is a symptom with serious consequences, including higher risk of accidents and, in the case of obstructive sleep apnea, hypertension, stroke, myocardial infarction, and death. An algorithm for office-based evaluation, indications for further testing, and sleep lab testing methods are described.     

B and T cells are required for mouse mammary tumor virus spread within the mammary gland

Mouse mammary tumor virus (MMTV) is an infectious retrovirus transmitted through milk from mother to newborns. MMTV encodes a superantigen (SAg) whose activity is indispensable for the virus life cycle, since a genetically engineered virus with a mutation in the sag gene neither amplified in cells of the immune system of suckling pups nor infected their mammary glands. When wild-type MMTV was injected directly into the mammary glands of uninfected pubescent mice, their lymphoid as well as mammary gland cells became virus infected. To test whether this infection of lymphoid cells was dependent on SAg activity and required for virus spread within the mammary gland, we performed mammary gland injections of wild-type MMTV(C3H) into two strains of transgenic mice that lacked SAg-cognate, V beta 14+ T cells. Neither the MTV-ORF or LEL strains showed infection of their mammary glands. Moreover, no MMTV infection of their peripheral lymphocytes was detected. Similar experiments with mice lacking B cells (mu-chain knockouts) showed no detectable virus spread in the mammary glands or lymphoid tissues. These data suggest that SAg activity and MMTV-infected lymphocytes are required, not only for initial steps of viral infection, but also for virus spread within the mammary gland. Virus spread at late times in infection determines whether MMTV induces mammary tumors.     

Base stacking: pH-mediated on-column sample concentration for capillary DNA sequencing

An on-column sample concentration method for capillary-based DNA sequencing was studied. This base-stacking method allows direct injection of unpurified products of dye-primer sequencing reactions onto capillaries without any pretreatment. On-column concentration of DNA fragments is achieved simply by electrokinetic injection of hydroxide ions. A neutralization reaction between these OH- ions and the cationic buffer component Tris+ results in a zone of lower conductivity, within which field focusing occurs. DNA fragments are concentrated at the front of this low-conductivity zone. With sample injection times as long as 360 s at 50 V/cm, resolution could still be restored by the stacking process. Using a 36/47-cm-long uncoated capillary, with poly(dimethylacrylamide) as the separation matrix, and electric field of 160 V/cm, a resolution of at least 0.5 could be generated for fragments up to 650 nucleotides long. Both resolution and signal strength are excellent relative to conventional injection of highly purified samples. No significant degradation of the capillary performance was observed over at least 20 sequencing runs using this new sample injection methods.