First rotavirus vaccine licensed: Is there really a need?

The first rotavirus vaccine was licensed in the United States on 31 August 1998 for the prevention of severe rotavius diarrhea in children. Despite this landmark in new vaccines, many pediatricians and public health professionals in Europe are uncertain of the need for this vaccine for the routine immunization of infants. In Europe, ample evidence suggests that rotavirus is the most common cause of hospitalizations for severe diarrhea among children, but proper studies documenting the disease burden of rotavirus or th cost-effectiveness of a rotavirus immunization program have only been conducted in the United Kingdom following epidemiologic models used in the United States. All children are infected with rotavirus during their first few years of life, 30-50% of diarrheal hospitalizations among children <5 years are due to this agent, and, by the age of 5 years, between 1 in 40 and 1 in 77 children in Europe and the United States may be hospitalized for rotavirus. The first vaccine is a live, oral preparation combining four different serotypes of rotavirus and administered in three doses with other childhood immunizations. The good efficacy against severe rotavirus diarrhea, the low risk of adverse side effects and the positive costeffectiveness equation have led the two major immunization advisory groups in the U.S. to recommend this vaccine for routine use in American infants. European physicians and policymakers should re-examine the epidemiology and disease burden of rotavirus diarrhea now that an effective method of prevention is at hand. □ Childhood immunization, diseases, rotavirus, vaccination .     

A novel mutation in MED12 causes FG syndrome (Opitz–Kaveggia syndrome)

Rump P, Niessen RC, Verbruggen KT, Brouwer OF, de Raad M, Hordijk R. A novel mutation in MED12 causes FG syndrome (Opitz–Kaveggia syndrome). Opitz–Kaveggia syndrome is a rare X‐linked multiple congenital anomalies and intellectual disability disorder caused by the recurrent p.R961W mutation in the MED12 gene. Twenty‐three affected males from 10 families with this mutation in the MED12 gene have been described so far. Here we report on a new family with three affected cousins, in which we identified a novel MED12 mutation (p.G958E). This is the first demonstration that other mutations in this gene can also lead to Opitz–Kaveggia syndrome. The clinical phenotype of these three new cases is reviewed in detail and compared with the previous reported cases.     

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

Quantitative detection of RASSF1A DNA promoter methylation in tumors and serum of patients with serous epithelial ovarian cancer

Objective

Detection of cell free tumor-specific DNA methylation has been proposed as a potentially useful noninvasive mechanism to detect malignancies, including ovarian cancer, and to monitor response to treatment. However, there are few easily implemented quantitative approaches available for DNA methylation analysis. Our objectives were to develop an absolute quantitative method for detection of DNA methylation using RASSF1A, a known target of promoter methylation in ovarian cancer, and test the ability to detect RASSF1A methylation in tumors and serum specimens of women with ovarian cancer.

Methods

Bisulfite modified DNAs were subjected to real time PCR using nondiscriminatory PCR primers and a probe with sequence containing a single CpG site, theoretically able to capture the methylation status of that CpG for every allele within a given specimen. Input DNA was normalized to ACTB levels detected simultaneously by assay multiplexing. Methylation levels were established by comparison to results obtained from universally methylated DNA.

Results

The assay was able to detect one methylated RASSF1A allele in 100,000 unmethylated alleles. RASSF1A was methylated in 54 of 106 (51%) invasive serous ovarian cancers analyzed and methylation status was concordant in 20/20 matched preoperative serum-tumor pairs. Serial serum specimens taken over the course of treatment for 8 of 9 patients showed fluctuations in RASSF1A methylation concomitant with disease status.

Conclusions

This novel assay provides a real-time PCR-based method for absolute quantitation of DNA methylation. Our results support feasibility of monitoring RASSF1A methylation from serum samples taken over the course of treatment from women with ovarian cancer.     

Consensus guidelines on analgesia and sedation in dying intensive care unit patients

Background

Intensivists must provide enough analgesia and sedation to ensure dying patients receive good palliative care. However, if it is perceived that too much is given, they risk prosecution for committing euthanasia. The goal of this study is to develop consensus guidelines on analgesia and sedation in dying intensive care unit patients that help distinguish palliative care from euthanasia.

Methods

Using the Delphi technique, panelists rated levels of agreement with statements describing how analgesics and sedatives should be given to dying ICU patients and how palliative care should be distinguished from euthanasia. Participants were drawn from 3 panels: 1) Canadian Academic Adult Intensive Care Fellowship program directors and Intensive Care division chiefs (N = 9); 2) Deputy chief provincial coroners (N = 5); 3) Validation panel of Intensivists attending the Canadian Critical Care Trials Group meeting (N = 12).

Results

After three Delphi rounds, consensus was achieved on 16 statements encompassing the role of palliative care in the intensive care unit, the management of pain and suffering, current areas of controversy, and ways of improving palliative care in the ICU.

Conclusion

Consensus guidelines were developed to guide the administration of analgesics and sedatives to dying ICU patients and to help distinguish palliative care from euthanasia.     

Presence of mouse mammary tumour-like virus gene sequences may be associated with morphology of specific human breast cancer

BACKGROUND: Mouse mammary tumour virus (MMTV) has a proven role in breast carcinogenesis in wild mice and genetically susceptible in-bred mice. MMTV-like env gene sequences, which indicate the presence of a replication-competent MMTV-like virus, have been identified in some human breast cancers, but rarely in normal breast tissues. However, no evidence for a causal role of an MMTV-like virus in human breast cancer has emerged, although there are precedents for associations between specific histological characteristics of human cancers and the presence of oncogenic viruses. AIM: To investigate the possibility of an association between breast cancer and MMTV-like viruses. METHODS: Histological characteristics of invasive ductal human breast cancer specimens were compared with archival MMTV-associated mammary tumours from C3H experimental mice. The presence of MMTV-like env DNA sequences in the human breast cancer specimens was determined by polymerase chain reaction and confirmed by Southern hybridisation. RESULTS: MMTV-like env gene sequences were identified in 22 of 59 (37.3%) human breast cancer specimens. Seventeen of 43 (39.5%) invasive ductal carcinoma breast cancer specimens and 4 of 16 (25%) ductal carcinoma in situ specimens had some histological characteristics, which were similar to MMTV-associated mouse mammary tumours. However, these similarities were not associated with the presence or absence of MMTV-like gene sequences in the human breast tumour specimens. A significant (p = 0.05) correlation was found between the grade of the human breast cancer and similarity to the mouse mammary tumours. The lower the grade, the greater the similarity. CONCLUSION: Some human breast cancer specimens, in which MMTV-like env DNA sequences have been identified, were shown to have histological characteristics (morphology) similar to MMTV-associated mouse mammary tumours. These observations are compatible with, but not conclusive of, an association between the presence of MMTV-like env DNA sequences and some human breast cancers.