Gene-nutrient interactions in one-carbon metabolism

Advances in molecular biology greatly contributed, in the past decades, to a deeper understanding of the role of gene function in disease development. Environmental as well as nutritional factors are now well acknowledged to interact with the individual genetic background for the development of several diseases, including cancer, cardiovascular disease, and neurodegenerative diseases. The precise mechanisms of such gene-nutrient interactions, however, are not fully elucidated yet. Many micronutrients and vitamins are crucial in regulating mechanisms of DNA metabolism. Indeed, folate has been most extensively investigated for its unique function as mediator for the transfer of one-carbon moieties for nucleotide synthesis/repair and biological methylation. Cell culture, animal, and human studies, clearly demonstrated that folate deficiency induces disruption of DNA synthesis/repair pathways as well as DNA methylation anomalies. Remarkably, a gene-nutrient interaction between folate status and a polymorphism in methylenetetrahydrofolate reductase gene has been reported to modulate genomic DNA methylation. This observation suggests that the interaction between a nutritional status and a mutant genotype may modulate gene expression through DNA methylation, especially when such polymorphism affects a key enzyme in one-carbon metabolism and limits the methyl supply. DNA methylation, both genome-wide and gene-specific, is of particular interest for the study of aging, cancer, and other pathologic conditions, because it affects gene expression without permanent alterations in the DNA sequence such as mutations or allele deletions. Understanding the patterns of DNA methylation through the interaction with nutrients is a critical issue, not only to provide pathophysiological explanations of a disease state, but also to identify individuals at-risk to conduct targeted diet-based interventions.     

Improving the reproducibility of diagnosing micrometastases and isolated tumor cells

BACKGROUND: The latest edition of the tumor-lymph node-metastasis (TNM) classification of malignant tumors distinguishes between isolated tumor cells (pN0) and micrometastases (pN1mi). The reproducibility of these categories has not been assessed previously. METHODS: Digital images from 50 cases with low-volume lymph node involvement from axillary sentinel lymph nodes were circulated twice for evaluation (Evaluation Rounds 1 and 2) among the members of the European Working Group for Breast Screening Pathology, and the members were asked to categorize lesions as micrometastasis, isolated tumor cells, or something else and to classify each case into a pathologic lymph node (pN) category of the pathologic TNM system. Methods for improving the low reproducibility of the categorizations were discussed between the two evaluation rounds. kappa Statistics were used for the assessment of interobserver variability. RESULTS: The kappa value for the consistency of categorizing low-volume lymph node load into micrometastasis, isolated tumor cells, or neither of those changed from 0.39 to 0.49 between Evaluation Rounds 1 and 2, but it was slightly lower for the pN categories (0.35 and 0.44, respectively). Interpretation of the definitions of isolated tumor cells (especially with respect to their localization within the lymph node), lack of guidance on how to measure them if they were multiple, and lack of any definitions for multiple simultaneous foci of lymph node involvement were listed among the causes of discordant diagnoses. CONCLUSIONS: The results of the current study indicated that the definitions available have minor contradictions and do not permit a reproducible distinction between micrometastases and isolated tumor cells. Refinement of these definitions, therefore, is required. One refinement that may improve reproducibility is suggested in this report.     

Removal of an unexpected tracheal foreign body after five months

Foreign body aspiration can produce serious pulmonary diseases. Timely diagnosis and appropriate treatment is important to prevent long-term complications in affected children. We report the case of a 15-month-old child with a 5-month history of regurgitation, vomiting, recurrent tracheobronchitis, and pneumonia. The diagnosis was gastroesophageal reflux. The laryngotracheal endoscopy revealed a rabbit vertebra partially obstructing the airway at the level of the cricoid cartilage. With a rigid bronchoscope and forceps equipped with a telescope, it was possible to disengage and extract the foreign body. Six months later endoscopic control revealed no residual alterations in the larynx and trachea.     

Motor impairment on awakening in a patient with an EEG pattern of "unilateral, continuous spikes and waves during slow sleep".

Movement disorders are rarely described in association with the "continuous spikes and waves during slow sleep (CSWS)" EEG pattern. We report the case of a young girl affected by an epileptic encephalopathy who, from the age of seven years and four months, has twice presented a movement disorder affecting the right arm, manifesting on awakening and disappearing by early afternoon. Sleep EEG during these periods showed continuous, high-amplitude, diphasic spikes and slow waves over the left hemisphere. Association of clobazam, valproic acid and, on the second occasion, ethosuccimide led to disappearance of the above-described EEG picture and associated motor symptoms. Neurophysiological investigations excluded other possible aetiologies. In view of this, and of the close relationship between the EEG picture and clinical course, we interpret the patient's impairment as "motor neglect" secondary to the continuous electrical activity recorded during sleep over the left hemisphere and involving the associative areas. This electrical activity in sleep, may be regarded as a "functional lesion" whose clinical consequences can be correlated with the site of the abnormalities.[Published with video sequences].     

Efficacy of bortezomib therapy for extramedullary relapse of myeloma after autologous and non-myeloablative allogeneic transplantation

We report the successful use of bortezomib to treat a patient with multiple myeloma (MM) who had extramedullary relapse (paraspinal and thoracic masses and multiple cranial nerve palsy) after autologous and non-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT).     

A pilot study of nurse-led, home-based telecardiology for patients with chronic heart failure

We assessed the feasibility of home-based telecardiology for patients with chronic heart failure (CHF). Seventy-four CHF patients were enrolled into a programme of telephone follow-up and single-lead electrocardiography (ECG) monitoring. The patients transmitted their ECG data by fixed telephone line to a receiving station, where a nurse was available for an interactive teleconsultation. Patients were followed up for a mean (SD) of 307 (108) days; 1467 calls were analysed (213 ad hoc consultations and 1254 scheduled consultations). A total of 124 cardiovascular events were recorded. Modifications to therapy were suggested in response to 119 calls; hospital admissions were suggested for 13 patients, further investigations for 7 and a consultation with the patient's general practitioner for 13. No action was taken after 1330 calls. Twenty-two ECG abnormalities were recorded. In 63 patients receiving the beta-blocker carvedilol, the mean dosage increased from 36 to 42 mg. In the previous year there were 1.8 hospitalizations per patient, while in the follow-up period there were 0.2 hospitalizations per patient. Following up CHF patients using a nurse-led telecardiology programme seems to be feasible and useful.     

Benign breast diseases in breast cancer screening programs in Italy (2000-2001)

AIMS AND BACKGROUND: Screening mammography has been shown to be effective in reducing breast cancer mortality in several randomized clinical trials. One major side effect of screening is the diagnosis of benign breast disease (BBD), which is considered as a nonprogressive lesion, except for a small percentage of lesions considered at high risk. We present data referring to service screening programs active in Italy in 2000 and 2001 and participating in the national survey carried out by the Italian Group for Mammography Screening (GISMa). METHODS: To all centers participating in the GISMa National Survey, we submitted a questionnaire regarding the service screening protocol and main indicators of performance of the local program in the years 2000 and 2001. RESULTS: A total of 657 detected BBD cases, registered by 23 Italian breast cancer screening centers in women 50 to 69 years of age, are included in this study. The BBD detection rate was 2.5 per 1000 at the first screening test and 1.05 per 1000 at repeated tests. The benign/malignant ratio was 0.34 at the first and 0.22 at the repeated test. CONCLUSIONS: Detection of BBD occurred frequently in breast screening programs, and prognostic implications should be further investigated. Women should be individually informed at screening, and with greater detail at the moment of the recall for assessment, of the implications of BBD detection and receive the necessary, also psychological, counseling to avoid the possible harm related to breast cancer screening.