Role of Adjuvant Radiotherapy in Acinic Cell Carcinoma of the Salivary Glands: A Systematic Review.

A systematic review was carried out to evaluate if adjuvant radiotherapy for acinic cell carcinomas (ACCs) of salivary glands improves survival. Twelve retrospective studies published between 2000 and 2020 that analysed the effect of radiotherapy on salivary gland neoplasms and ACCs of salivary glands and met the inclusion criteria were included in the review. The overall quality of the studies was moderate to low. There was no high-quality evidence for improved survival with radiotherapy for ACCs of the salivary gland. Some evidence suggests that there may be an advantage for patients with high-grade tumours, but these data should be interpreted with caution due to the small number of patients and low-quality evidence. Good quality of evidence is lacking. Recommendation for adjuvant radiotherapy for tumours with poor prognostic factors will require discussion and shared decision-making with the patients.

Reducing donor-site complications in DIEP flap breast reconstruction with closed incisional negative pressure therapy: A cost-benefit analysis.

INTRODUCTION: Deep inferior epigastric perforator (DIEP) flaps are considered the gold standard for autologous breast reconstruction but create large abdominal incisions that risk donor-site morbidity during harvest. Closed incision negative pressure therapy (ciNPT) is emerging as an effective alternative to standard postoperative dressings, but there is a paucity of data in DIEP flap donor sites. METHODS: We conducted a retrospective case-control study investigating the use of ciNPT in DIEP flap donor sites at a single institution between March 2017 and September 2021. Patients who underwent microsurgical autologous breast reconstruction with DIEP flaps were included. Patients were divided into those with donor incision sites managed with ciNPT (n = 24) and those with conventional postoperative wound dressings (n = 20). We compared patient demographics, wound drainage volumes and postoperative outcomes between the two groups. A cost-benefit analysis was employed to compare the overall costs associated with each complication and differences in length of stay between the two groups. RESULTS: There was no statistically significant difference in age, body mass index (BMI), comorbidity burden or smoking status between the two groups. Both groups had similar lengths of stay and wound drainage volumes with no readmissions or reoperations in either group. There was a statistically significant reduction in donor-site complications (p = 0.018), surgical site infections (p = 0.014) and seroma formation (p = 0.016) in those with ciNPT. Upon cost-benefit analysis, the ciNPT group had a mean reduction in cost-per-patient associated with postoperative complications of £420.77 (p = 0.031) and £446.47 (p = 0.049) when also accounting for postoperative length of stay CONCLUSION: ciNPT appears to be an effective alternative incision management system with the potential to improve complication rates and postoperative morbidity in DIEP flap donor sites. Our analysis demonstrates improved cost-benefit outweighing the increase in costs associated with ciNPT. We recommend a multicentre prospective trial with formal cost-utility analysis to strengthen these findings.

Bleeding gastric ulcer from a pulmonary artery 20 years post-oesophagectomy: a common presentation with a rare cause.

This case presents an unusually late complication of oesophagectomy 20-years post-surgery, with upper gastrointestinal bleeding. Further investigation revealed a gastric conduit ulcer eroding into the lower lobe of the right lung, forming a fistula with a basal branch of the right pulmonary artery. Upon successful embolisation, the HydroCoil® was visible on endoscopy. This case highlights the need for lifetime proton pump inhibitor cover post-oesophagectomy and demonstrates that when approaching uncommon presentations of common problems, careful consideration to treatment technique is essential.

Pleiotropic effect of somatic mutations in the E2F subunit DP-1 gene in human cancer.

Transcription factor E2F-1 and its interaction with pRb provide a key point of control in cell proliferation. E2F-1 participates in both cell cycle progression and apoptosis, and in cells exists with a DP dimerization partner protein, the most prominent being DP-1. By mining the tumor tissue and cancer cell line encyclopedia genomic databases, we identified the first somatic mutations in the DP-1 gene and describe 53 distinct mutation events here. The mutations are mostly missense mutations, but also include nonsense and frame-shift mutations that result in truncated DP-1 derivatives. Mutation occurs throughout the DP-1 gene but generally leaves protein dimerization activity intact. This allows the mutant derivatives to affect the properties of the E2F-1/DP-1 heterodimer through a transdominant mechanism, which changes the DNA binding, transcriptional activation and pRb-binding properties of the heterodimer. In particular, many DP-1 mutants were found to impair E2F-1-dependent apoptosis. Our results establish that somatic mutations in DP-1 uncouple normal control of the E2F pathway, and thus define a new mechanism that could contribute to aberrant proliferation in tumor cells.

Histone deacetylase inhibition by trichostatin A mitigates LPS induced TNFα and IL-10 production in human placental explants.

INTRODUCTION: Cytokine expression by the placenta is known to change across pregnancy, and is altered in a number of pathologies; however the precise mechanisms of cytokine regulation in gestational tissues are not well understood. It has been previously reported that cytokine protein production in gestational tissues is regulated in a tissue-specific manner and appears to be epigenetically regulated. METHODS: In this study we investigated changes in cytokine mRNA expression and protein production by term placental explants maintained at 8% O2 in the presence or absence of lipopolysaccharide (LPS) (5 µg/mL) and the histone deacetylase inhibitor trichostatin A (TSA) (300 nM). RESULTS: As expected, exposure to LPS stimulated gene expression and protein production of the proinflammatory cytokines IL-1ß, IL-6, IL-8 and TNFα, as well as the anti-inflammatory cytokine IL-10. While TSA alone had little effect, TSA co-treatment mitigated the effects of LPS on TNFα and IL-10 protein production with an accompanying reduction in TNFα mRNA transcript levels detected. However, TSA had no significant effect on LPS induced IL-1ß, IL-1ra, IL-6 or IL-8 mRNA expression or protein production. DISCUSSION: The data from this study show that TSA selectively mitigates the stimulatory effect of LPS on TNFα mRNA expression, TNFα protein production and IL-10 protein production. As there is no compensatory effect on IL-1ß, IL-1ra, IL-6, or IL-8 mRNA expression or protein production, this results in a dysregulation of the cytokine balance. CONCLUSIONS: Insights into HDAC regulation of cytokine expression may provide novel therapeutic strategies for conditions associated with dysregulation of the cytokine network, such as preeclampsia and infection mediated preterm labor.

Diversity within the pRb pathway: is there a code of conduct?

The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein (pRb) pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post-translational modifications that occur on pRb together with its key effector E2F-1. Here we provide an overview of the modifications and consider the possibility of a 'code' that endows pRb with the ability to function in diverse physiological settings.

E2F-1 regulation by an unusual DNA damage-responsive DP partner subunit.

E2F activity is negatively regulated by retinoblastoma protein (pRb) through binding to the E2F-1 subunit. Within the E2F heterodimer, DP proteins are E2F partner subunits that allow proper cell cycle progression. In contrast to the other DP proteins, the newest member of the family, DP-4, downregulates E2F activity. In this study we report an unexpected role for DP-4 in regulating E2F-1 activity during the DNA damage response. Specifically, DP-4 is induced in DNA-damaged cells, upon which it binds to E2F-1 as a non-DNA-binding E2F-1/DP-4 complex. Consequently, depleting DP-4 in cells re-instates E2F-1 activity that coincides with increased levels of chromatin-bound E2F-1, E2F-1 target gene expression and associated apoptosis. Mutational analysis of DP-4 highlighted a C-terminal region, outside the DNA-binding domain, required for the negative control of E2F-1 activity. Our results define a new pathway, which acts independently of pRb and through a biochemically distinct mechanism, involved in negative regulation of E2F-1 activity.

Epigenetic regulation of endometrium during the menstrual cycle.

The endometrium undergoes morphological and functional changes during the menstrual cycle which are essential for uterine receptivity. These changes are driven by estrogen and progesterone and involve the fine control of many different genes-several of which have been identified as being epigenetically regulated. Epigenetic modification may therefore influence the functional changes in the endometrium required for successful implantation. There is, however, only limited information on epigenetic regulation in endometrium. We review the potential role of epigenetic regulation of key processes during the menstrual cycle and present our own findings following a preliminary study into global acetylation levels in the human endometrium. A changing epigenetic state is associated with the differentiation of stem cells into different lineages and thus may be involved in endometrial regeneration. Histone acetylation is implicated in the vascular endothelial growth factor pathway during angiogenesis, and studies using histone deacetylase inhibitors suggest an involvement in endometrial proliferation and differentiation. The processes of decidualization and implantation are also associated with epigenetic change and epigenetic modulators show variable expression across the menstrual cycle. Our own studies found that endometrial global histone acetylation, as determined by western blotting, changed throughout the menstrual cycle and correlated well with expected transcription activity during the different phases. This suggests that epigenetics may be involved in the regulation of endometrial gene expression during the menstrual cycle and that abnormal epigenetic modifications may therefore be associated with implantation failure and early pregnancy loss as well as with other endometrial pathologies.

Lysine methylation regulates the pRb tumour suppressor protein.

The pRb tumour suppressor protein has a central role in coordinating early cell cycle progression. An important level of control imposed on pRb occurs through post-translational modification, for example, phosphorylation. We describe here a new level of regulation on pRb, mediated through the targeted methylation of lysine residues, by the methyltransferase Set7/9. Set7/9 methylates the C-terminal region of pRb, both in vitro and in cells, and methylated pRb interacts with heterochromatin protein HP1. pRb methylation is required for pRb-dependent cell cycle arrest and transcriptional repression, as well as pRb-dependent differentiation. Our results indicate that methylation can influence the properties of pRb, and raise the interesting possibility that methylation modulates pRb tumour suppressor activity.

Surveying the attitudes of acute mental health nurses.

Recent UK policy and guidance indicates the importance of positive attitudes towards mental health service users. This is especially true in acute inpatient care, where service users are often at their most vulnerable and have higher levels of contact with mental health staff. The following paper details secondary analysis of data collected for the validation of an attitude measurement scale with a sample of 140 nursing staff in acute settings. The results demonstrate that a wide range of attitudes are held by mental health nurses towards acute mental health care. Overall, the results indicate generally positive attitudes. Significant differences were found between qualified and unqualified staff, and males and females for some questions. Recommendations are made for future attitudinal research of mental health staff.

Childhood unintentional injuries: the perceived impact of the environment, lack of supervision and child characteristics.

BACKGROUND: Investigations into the context and causation of injury, including injury risks, are an essential part of the injury prevention knowledge base. Caregiver perceptions of childhood injury risks may assist in the design of safety interventions and influence the way in which an intervention is received within a community. METHODS: Focus groups and individual interviews were conducted in two low-income neighbourhoods in South Africa to collect information on caregiver perceptions of injury risks. The data were analysed via thematic content analysis. RESULTS: The results revealed that injury risks are perceived as multifaceted and as contributing synergistically to an injury event. Parents of children also tended to attribute most risks to the environment instead of individual action. CONCLUSIONS: Interventions including passive strategies and less activity from the parent may be welcomed in communities. Attention should be given to child injury prevention methods specifically for low-income contexts.

Correlates of placental infection with cytomegalovirus, parvovirus B19 or human herpes virus 7.

Vertical transmission of viruses is an important cause of morbidity in the fetus and neonate. Placental viral infection indicates risk of vertical transmission, but not always transmission to, or disease of the fetus. Specimens from mothers and babies from three groups-two prospective and one retrospective cohort-were tested for pathogens of teratogenic potential using multiplex PCR. Placental infection was present in 13% of the 105 samples collected. Assessment of the prospective cohorts showed cytomegalovirus (CMV) detected in 4% of placentae from unselected women, parvovirus B19 in 1% and Ureaplasma parvum in 1% of placentae. In a retrospective cohort of women at high risk of transmitting congenital infection due to seroconversion during pregnancy, miscarriage or stillbirth, CMV was detected in 64% and human herpes virus type 7 in 9% of placentae. Of 14 PCR-positive placentae, two were associated with the birth of a living symptomatic infant, two with stillbirth, one with miscarriage, and two with elective terminations of pregnancy. Directed laboratory assessment of women at high risk of transmitting congenital infection, on the basis of clinical or laboratory markers, is important for accurate diagnosis of adverse outcomes of pregnancy. However, routine screening for viruses in the placentae from women with a low-risk serological profile for transmitting congenital infection is unlikely to result in significant numbers of additional diagnoses and is confounded by inadequacy of current diagnostic methods. The major pathogen detected in all cases of placental infection associated with fetal death was human CMV.

A functionally distinct member of the DP family of E2F subunits.

E2F transcription factors regulate genes involved in cell-cycle progression. In mammalian cells, physiological E2F exists as an E2F/DP heterodimer. Currently, eight E2F and two DP subunits have been characterized. We report here the characterization of a new member of the DP family, DP-4. While DP-4 exhibits certain similarities with members of the DP family, it also possesses a number of significant differences. Thus, DP-4 forms a heterodimer with E2F subunits, binds to the E2F site and associates with pocket proteins including pRb. In contrast to DP-1, however, DP-4/E2F-1 complexes exhibit reduced DNA binding activity. Furthermore, DP-4 interferes with E2F-1-dependent transcription and delays cell-cycle progression. These results highlight an emerging complexity in the DP family of E2F subunits, and suggest that DP-4 may endow E2F heterodimers with distinct transcription properties.

Development of multiplex PCRs for detection of common viral pathogens and agents of congenital infections.

Potential causes of congenital infection include Toxoplasma gondii and viruses such as cytomegalovirus (CMV), enterovirus, hepatitis C virus, herpes simplex virus types 1 and 2 (HSV-1 and -2), human herpesvirus types 6, 7, and 8, lymphocytic choriomeningitis virus, parvovirus, rubella virus, and varicella-zoster virus. Testing for each of these agents using nucleic acid tests is time consuming and the availability of clinical samples such as amniotic fluid or neonatal blood is often limited. The aim of this study was to develop multiplex PCRs (mPCRs) for detection of DNA and RNA agents in the investigation of congenital infection and an mPCR for the viruses most commonly requested in a diagnostic virology laboratory (CMV, Epstein-Barr virus, enterovirus, HSV-1, HSV-2, and varicella-zoster virus). The assays were assessed using known pathogen-positive tissues (cultures, placentae, plasma, and amniotic fluid) and limits of detection were determined for all the agents studied using serial dilutions of plasmid targets. Nested PCR was performed as the most sensitive assay currently available, and detection of the amplicons using hybridization to labeled probes and enzyme-linked immunosorbent assay detection was incorporated into three of the four assays. This allowed detection of 10 to 10(2) copies of each agent in the samples processed. In several patients, an unexpected infection was diagnosed, including a case of encephalitis where HSV was the initial clinical suspicion but CMV was detected. In the majority of these cases the alternative agent could be confirmed using reference culture, serology, or fluorescence methods and was of relevance to clinical care of the patient. The methods described here provide useful techniques for diagnosing congenital infections and a paradigm for assessment of new multiplex PCRs for use in the diagnostic laboratory.

Diagnosis of and screening for cytomegalovirus infection in pregnant women.

No single diagnostic test for cytomegalovirus (CMV) infection is currently available for pregnant women at all stages of gestation. Improved accuracy in estimating the timing of primary infections can be used to identify women at higher risk of giving birth to congenitally infected infants. A diagnostic algorithm utilizing immunoglobulin G (IgG), IgM, and IgG avidity was used to prospectively screen serum from 600 pregnant women enrolled from two groups: < or =20 weeks gestation (n = 396) or >20 weeks gestation (n = 204). PCR testing of urine and/or blood was performed on all seropositive women (n = 341). The majority (56.8%) of women were CMV IgG seropositive, with 5.5% being also CMV IgM positive. In the IgM-positive women, 1.2% had a low-avidity IgG, indicating a primary CMV infection and a high risk of intrauterine transmission. Two infants with asymptomatic CMV infection were born of mothers who had seroconverted in the second trimester of pregnancy. Baseline, age-stratified CMV serostatus was established from 1,018 blood donors. Baseline seropositivity from a blood donor population increased with age from 34.9% seroprevalence at less than 20 years of age to 72% seroprevalence at 50 years of age. Women at high risk of intrauterine transmission of CMV were identified at all stages of gestation. Women infected with CMV during late gestation may be more likely to transmit the virus, so failure to detect seroconversions in late gestation may result in failure to detect infected neonates.

The Arf-like GTPase Arl1 and its role in membrane traffic.

Small GTP-binding proteins of the Rab and Arf (ADP-ribosylation factor) families play a central role in the membrane trafficking pathways of eukaryotic cells. The prototypical members of the Arf family are Arf1-Arf6 and Sar1, which have well-characterized roles in membrane traffic or cytoskeletal reorganization. However, eukaryotic genomes encode additional proteins, which share the characteristic structural features of the Arf family, but the role of these 'Arf-like' (Arl) proteins is less well understood. This review discusses Arl1, a GTPase that is widely conserved in evolution, and which is localized to the Golgi in all species so far examined. The best-characterized effectors of Arl1 are coiled-coil proteins which share a C-terminal GRIP domain, but other apparent effectors include the GARP (Golgi-associated retrograde protein)/VFT (Vps fifty-three) vesicle-tethering complex and Arfaptin 2. As least some of these proteins are believed to have a role in membrane traffic. Genetic analysis in a number of species has shown that Arl1 is not essential for exocytosis, but rather suggest that it is required for traffic from endosomes to the Golgi.

Characterization of Salmonella enterica serotype newport isolated from humans and food animals.

Salmonella enterica serotype Newport isolates resistant to at least nine antimicrobials (including extended-spectrum cephalosporins), known as serotype Newport MDR-AmpC isolates, have been rapidly emerging as pathogens in both animals and humans throughout the United States. Resistance to extended-spectrum cephalosporins is associated with clinical failures, including death, in patients with systemic infections. In this study, 87 Salmonella serotype Newport strains were characterized by pulsed-field gel electrophoresis (PFGE) and antimicrobial susceptibility testing and examined for the presence of class 1 integrons and bla(CMY) genes. Thirty-five PFGE patterns were observed with XbaI, and three of these patterns were indistinguishable among isolates from humans and animals. Fifty-three (60%) Salmonella serotype Newport isolates were identified as serotype Newport MDR-AmpC, including 16 (53%) of 30 human isolates, 27 (93%) of 29 cattle isolates, 7 (70%) of 10 swine isolates, and 3 (30%) of 10 chicken isolates. However, 28 (32%) Salmonella serotype Newport isolates were susceptible to all 16 antimicrobials tested. The bla(CMY) gene was present in all serotype Newport MDR-AmpC isolates. Furthermore, the plasmid-mediated bla(CMY) gene was transferable via conjugation to an Escherichia coli strain. The transconjugant showed the MDR-AmpC resistance profile. Thirty-five (40%) of the isolates possessed class 1 integrons. Sequence analyses of the integrons showed that they contained aadA, which confers resistance to streptomycin, or aadA and dhfr, which confer resistance to trimethoprim-sulfamethoxazole. One integron from a swine isolate contained the sat-1 gene, which encodes resistance to streptothricin, an antimicrobial agent that has never been approved for use in the United States. In conclusion, Salmonella serotype Newport MDR-AmpC was commonly identified among Salmonella serotype Newport isolates recovered from humans and food animals. These findings support the possibility of transmission of this organism to humans through the food chain.

The mandibular canal of the edentulous jaw.

The morphology of the mandibular canal after loss of teeth has received little detailed attention. Improved documentation of this topic would allow better interpretation of dental radiographs and would enable those engaged in tooth implantation to better understand the nature of the tissue into which the prostheses are placed. In this study on mandibles from seven dissecting room cadavers panoramic radiographs usually showed the mandibular canal clearly, an incisive canal less so. The wall of the mandibular canal was similar in dentate and edentulous mandibles, and was highly perforated, as suggested by Cryer (Anderson et al., 1991). In edentulous specimens, it was composed mainly of cancellous bone with only occasional single osteons. The inferior alveolar nerve near the mandibular foramen was a large trunk, consisting of three to four nerve bundles with connective tissue sheaths. It became more loosely arranged toward the mental foramen. Medial to the mental foramen, the nerves were frequently in the form of small bundles in the marrow. Any incisive canal was ill-defined and neurovascular bundles, when present, ran through a labyrinth of intertrabecular spaces.

The Sec34/35 Golgi transport complex is related to the exocyst, defining a family of complexes involved in multiple steps of membrane traffic.

The specificity of intracellular vesicle transport is mediated in part by tethering factors that attach the vesicle to the destination organelle prior to fusion. We have identified a protein, Dor1p, that is involved in vesicle targeting to the yeast Golgi apparatus and found it to be associated with seven further proteins. Identification of these revealed that they include Sec34p and Sec35p, the two known components of the Sec34/35 complex previously proposed to tether vesicles to the Golgi. Of the six previously uncharacterized components, four have homologs in higher eukaryotes, including a subunit of a mammalian Golgi transport complex. Furthermore, several of the proteins show distant homology to components of two other putative tethering complexes, the exocyst and the Vps52/53/54 complex, revealing that tethering factors involved in different membrane traffic steps are structurally related.