Suppression of tumor-derived Semaphorin 7A and genetic ablation of host-derived Semaphorin 7A impairs tumor progression in a murine model of advanced breast carcinoma.

Solid tumors can generate a plethora of neurogenesis-related molecules that enhance their growth and metastasis. Among them, we have identified axonal guidance molecule Semaphorin 7A (SEMA7A) in breast cancer. The goal of this study was to determine the therapeutic effect of suppressing SEMA7A levels in the 4T1 murine model of advanced breast carcinoma. We used anti-SEMA7A short hairpin RNA (shRNA) to gene silence SEMA7A in 4T1 mammary tumor cells. When implanted into the mammary fat pads of syngeneic mice, SEMA7A shRNA-expressing 4T1 tumors exhibited decreased growth rates, deferred metastasis and reduced mortality. In vitro, SEMA7A shRNA-expressing 4T1 cells had weakened proliferative, migratory and invasive abilities, and decreased levels of mesenchymal factors. Atomic force microscopy studies showed that SEMA7A shRNA-expressing 4T1 cells had an increase in cell stiffness that corresponded with their decreased malignant potential. Genetic ablation of host-derived SEMA7A further enhanced the antitumor effects of SEMA7A shRNA gene silencing in 4T1 cells. Our preclinical findings demonstrate a critical role for SEMA7A in mediating mammary tumor progression.

Comparing hospital and telephone follow-up for patients treated for stage-I endometrial cancer (ENDCAT trial): a randomised, multicentre, non-inferiority trial.

OBJECTIVE: To evaluate the effectiveness of nurse-led telephone follow-up (TFU) for patients with stage-I endometrial cancer. DESIGN: Multicentre, randomised, non-inferiority trial. SETTING: Five centres in the North West of England. SAMPLE: A cohort of 259 women treated for stage-I endometrial cancer attending hospital outpatient clinics for routine follow-up. METHODS: Participants were randomly allocated to receive traditional hospital based follow-up (HFU) or nurse-led TFU. MAIN OUTCOME MEASURES: Primary outcomes were psychological morbidity (State Trait Anxiety Inventory, STAI-S) and patient satisfaction with the information provided. Secondary outcomes included patient satisfaction with service, quality of life, and time to detection of recurrence. RESULTS: The STAI-S scores post-randomisation were similar between groups [mean (SD): TFU 33.0 (11.0); HFU 35.5 (13.0)]. The estimated between-group difference in STAI-S was 0.7 (95% confidence interval, 95% CI -1.9 to 3.3); the confidence interval lies above the non-inferiority limit (-3.5), indicating the non-inferiority of TFU. There was no significant difference between groups in reported satisfaction with information (odds ratio, OR 0.9; 95% CI 0.4-2.1; P = 0.83). Women in the HFU group were more likely to report being kept waiting for their appointment (P = 0.001), that they did not need any information (P = 0.003), and were less likely to report that the nurse knew about their particular case and situation (P = 0.005). CONCLUSIONS: The TFU provides an effective alternative to HFU for patients with stage-I endometrial cancer, with no reported physical or psychological detriment. Patient satisfaction with information was high, with similar levels between groups. TWEETABLE ABSTRACT: ENDCAT trial shows effectiveness of nurse-led telephone follow-up for patients with stage-I endometrial cancer.

HMGCR-associated myositis: a New Zealand case series and estimate of incidence.

Statins are one of the most commonly prescribed drugs in New Zealand, with 525 772 or 16.5% of the adult New Zealand population prescribed a statin between June 2013 and July 2014. While generally well-tolerated, statins are known to cause a range of muscle-related side effects, ranging from myalgia to life-threatening rhabdomyolysis. Recently, it has been recognised that in rare instances, statins can induce an immune-mediated necrotising myositis with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the enzymatic target of statins. In 2014, anti-HMGCR antibody testing was introduced to Canterbury Health Laboratories (CHL), with this being the only laboratory in New Zealand performing this test during the period of this case series. This article describes an index case and characterises the clinical features of a subsequent 12-month series. From this series, we estimated the yearly incidence of HMGCR-associated myositis at 1.7/million/year or ~1/90 000 New Zealand statin users.

Infrared spectroscopy with multivariate analysis to interrogate endometrial tissue: a novel and objective diagnostic approach.

BACKGROUND: Endometrial cancer is the most common gynaecological malignancy in the United Kingdom. Diagnosis currently involves subjective expert interpretation of highly processed tissue, primarily using microscopy. Previous work has shown that infrared (IR) spectroscopy can be used to distinguish between benign and malignant cells in a variety of tissue types. METHODS: Tissue was obtained from 76 patients undergoing hysterectomy, 36 had endometrial cancer. Slivers of endometrial tissue (tumour and tumour-adjacent tissue if present) were dissected and placed in fixative solution. Before analysis, tissues were thinly sliced, washed, mounted on low-E slides and desiccated; 10 IR spectra were obtained per slice by attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. Derived data was subjected to principal component analysis followed by linear discriminant analysis. Post-spectroscopy analyses, tissue sections were haematoxylin and eosin-stained to provide histological verification. RESULTS: Using this approach, it is possible to distinguish benign from malignant endometrial tissue, and various subtypes of both. Cluster vector plots of benign (verified post-spectroscopy to be free of identifiable pathology) vs malignant tissue indicate the importance of the lipid and secondary protein structure (Amide I and Amide II) regions of the spectrum. CONCLUSION: These findings point towards the possibility of a simple objective test for endometrial cancer using ATR-FTIR spectroscopy. This would facilitate earlier diagnosis and so reduce the morbidity and mortality associated with this disease.

A randomised controlled trial comparing two different local anaesthetic injection techniques prior to LLETZ.

The aim of this study was to compare two different anaesthetic injection techniques and assess whether one was less painful than the other when used prior to LLETZ. A total of 60 women undergoing LLETZ were randomised into two groups. The control group received local anaesthesia by deep injection into the substance of the cervix. The study group received an equivalent amount of local anaesthetic but this was injected superficially prior to deep injection into the cervix. Pain was assessed using a visual analogue scale. Women in the study arm experienced less pain than controls during injection of local anaesthetic.

Intrinsic ferromagnetism in CeO(2): dispelling the myth of vacancy site localization mediated superexchange.

Intrinsic ferromagnetism in CeO(2) is a source of controversy in the literature and has been linked to the excess electrons left over upon oxygen vacancy formation on Ce sites neighbouring the vacancy. A recent theoretical study (Han et al 2009 Phys. Rev. B 79 100403) concluded that increased vacancy concentration changes the localization behaviour of CeO(2), resulting in some degree of charge localization in the vacancy site itself, which leads to superexchange and polarization effects that enhance the stability of ferromagnetism. In this report, we show conclusively that oxygen vacancy concentrations of up to 12.5% do not cause localization in the vacancy site, and that this is not responsible for any enhanced ferromagnetism. Investigation of oxygen vacancies on the (111), (110) and (100) low index surfaces also show no evidence for ferromagnetic preference.

A case of torted parafimbrial cyst on MRI: case report and review of the literature.

Para-ovarian cysts (POCs) are an occasional finding at surgery, although they are rarely appreciated on imaging studies. Accurate diagnosis depends upon the demonstration of a para-ovarian location. We present the MR appearances of a torted POC in a fimbrial location, resembling a dermoid cyst.

Indels and imperfect duplication have driven the evolution of human Complement Receptor 1 (CR1) and CR1-like from their precursor CR1 alpha: importance of functional sets.

This study examines the effects of duplication and insertions-deletions (indels) by comparing human complement receptor 1 (CR1) and human CR1-like (CR1L) with syntenic genes from four other vertebrates (chimpanzee, baboon, rat, and mouse). By phylogenetic analysis, the domains of these genes can be classified into 10 distinct subfamilies (a, b, c, d, e, f, g(-like), h, j, and k), which have been largely conserved throughout vertebrate and invertebrate evolution. In spite of many complex and diverse duplications and indels, the subfamily order of domains (a, j, e, f, b, k, d, g(-like)) has been maintained. The number of domain sets has increased progressively, thereby expanding the functional repertoire.

Genomic analysis reveals a duplication of eight rather than seven short consensus repeats in primate CR1 and CR1L: evidence for an additional set shared between CR1 and CR2.

We report the discovery of previously unrecognised short consensus repeats (SCRs) within human and chimpanzee CR1 and CR1L. Analysis of available genomic, protein and expression databases suggests that these are actually genomic remnants of SCRs previously reported in other complement control proteins (CCPs). Comparison with the nucleotide motifs of the 11 defined subfamilies of SCRs justifies the designation g-like because of the close similarity to the g subfamily found in CR2 and MCP. To date, we have identified five such SCRs in human and chimpanzee CR1, one in human and chimpanzee CR1L, but none in either rat or mouse Crry in keeping with the number of internal duplications of the long homologous repeat (LHR) found in CR1 and CR1L. In fact, at the genomic level, the ancestral LHR must have contained eight SCRs rather than seven as previously thought. Since g-like SCRs are found immediately downstream of d SCRs, we suggest that there must have been a functional dg set which has been retained by CR2 and MCP but which is degenerate in CR1 or CR1L. Interestingly, dg is also present in the CR2 component of mouse CR1. The degeneration of the g SCR must have occurred prior to the formation of primate CR1L and prior to the duplication events which resulted in primate CR1. In this context, the apparent conservation of g-like SCRs may be surprising and may suggest the existence of mechanisms unrelated to protein coding. These results provide examples of the many processes which have contributed to the evolution of the extensive repertoire of CCPs.

Tricuspid atresia--profile and outcome.

Tricuspid atresia (TA) is the third most common cyanotic congenital cardiac lesion, with a mortality rate of 90% before the age of 10 years. Surgical intervention has reduced the mortality, but with unfavourable anatomy the mortality remains high. The aim of this study was to look at the profile of a cohort of children with TA and to evaluate treatment modalities and outcome. Twenty-seven children were included in this retrospective descriptive study. Twenty-three were referred with central cyanosis and 25% with cardiac failure. All patients had a left superior QRS axis on electrocardiogram (ECG). Eleven patients died, 8 before surgical intervention and 3 postoperatively. Outcome was mainly influenced by the anatomy of the pulmonary arteries especially when the pulmonary arteries were extremely hypoplastic. Patients with increased pulmonary blood flow did better than those with decreased pulmonary blood flow. There was a statistically significant difference in survival between the surgical and non-surgical groups. Few of our patients qualified for the Fontan procedure mainly because of increased pulmonary pressures in the high pulmonary blood flow group and severe hypoplastic pulmonary arteries in the low pulmonary blood flow group. Early referral is essential for palliation so that more definitive surgery can be done to achieve better results.

Oral antibodies to human papillomavirus type 16 in women with cervical neoplasia.

This study investigated the relationship between human papillomavirus type 16 (HPV-16) antibodies detected in oral fluid from women with cervical neoplasia, their HPV-16 antibody seroprevalence, and their cervical HPV-16 DNA presence. Cervical HPV-16 DNA was detected by polymerase chain reaction in 43.2% (35/81) of these women. The prevalence of IgG and IgA antibodies to HPV-16 virus-like particles (VLP-16) in oral fluid and was investigated by enzyme-linked immunosorbent assay. Anti-VLP-16 IgA antibodies were detected in oral fluid from 54.3% (44/81) of women with cervical neoplasia, compared with 8% (3/36) in controls (P = 0.000002). Anti-VLP-16 IgG was detected in oral fluid from 43.2.9% (25/72) and 13.3% (4/30; P = 0.029), respectively. Women who were HPV-16 DNA positive at their cervical lesion, displayed an oral fluid anti-VLP-16 IgA prevalence of 60.7% (17/28) and HPV-16 DNA negative women an oral fluid anti-VLP-16 IgA prevalence of 50% (20/40; P = 0.38). Oral fluid anti-VLP-16 IgG prevalence in HPV-16 DNA positive women was 28.6% (8/28) compared with 40% (16/40) in oral fluid from HPV-16 DNA negative women (P = 0.3). Amongst HPV-16 DNA positive women, the anti-VLP-16 IgG seroprevalence was 75% (21/28) and IgA seroprevalence 35.7% (10/28) and for the HPV-16 DNA negative women these values were 60% (24/40) and 32.5% (13/40), respectively. Oral IgA antibody testing proved no more sensitive than serum antibody detection for the determination of HPV infection but could be useful as a non-invasive screening method for women with cervical neoplasia and for estimating the mucosal antibody response to HPV vaccines.

Language deficits in dyslexic children: speech perception, phonology, and morphology.

We investigated the relationship between dyslexia and three aspects of language: speech perception, phonology, and morphology. Reading and language tasks were administered to dyslexics aged 8-9 years and to two normal reader groups (age-matched and reading-level matched). Three dyslexic groups were identified: phonological dyslexics (PD), developmentally language impaired (LI), and globally delayed (delay-type dyslexics). The LI and PD groups exhibited similar patterns of reading impairment, attributed to low phonological skills. However, only the LI group showed clear speech perception deficits, suggesting that such deficits affect only a subset of dyslexics. Results also indicated phonological impairments in children whose speech perception was normal. Both the LI and the PD groups showed inflectional morphology difficulties, with the impairment being more severe in the LI group. The delay group's reading and language skills closely matched those of younger normal readers, suggesting these children had a general delay in reading and language skills, rather than a specific phonological impairment. The results are discussed in terms of models of word recognition and dyslexia.

Are speech perception deficits associated with developmental dyslexia?

Phonological awareness and phoneme identification tasks were administered to dyslexic children and both chronological age (CA) and reading-level (RL) comparison groups. Dyslexic children showed less sharply defined categorical perception of a bath-path continuum varying voice onset time when compared to the CA but not the RL group. The dyslexic children were divided into two subgroups based on phoneme awareness. Dyslexics with low phonemic awareness made poorer /b/-/p/ distinctions than both CA and RL groups, but dyslexics with normal phonemic awareness did not. Examination of individual profiles revealed that the majority of subjects in each group exhibited normal categorical perception. However, 7 of 25 dyslexics had abnormal identification functions, compared to 1 subject in the CA group and 3 in the RL group. The results suggest that some dyslexic children have a perceptual deficit that may interfere with processing of phonological information. Speech perception difficulties may also be partially related to reading experience.

Articulatory strengthening at edges of prosodic domains.

In this paper it is shown that at the edges of prosodic domains, initial consonant and final vowels have more extreme (less reduced) lingual articulations, which are called articulatory strengthening. Linguopalatal contact for consonants and vowels in different prosodic positions was compared, using reiterant-speech versions of sentences with a variety of phrasings read by three speakers of American English. Four prosodic domains were considered: the phonological word, the phonological (or intermediate) phrase, the intonational phrase, and the utterance. Domain-initial consonants show more linguopalatal contact than domain-medial or domain-final consonants, at three prosodic levels. Most vowels, on the other hand, show less linguopalatal contact in domain-final syllables compared to domain-initial and domain-medial. As a result, the articulatory difference between segments is greater around a prosodic boundary, increasing the articulatory contrast between consonant and vowels, and prosodic domains are marked at both edges. Furthermore, the consonant initial strengthening is generally cumulative, i.e., the higher the prosodic domain, the more linguopalatal contact the consonant has. However, speakers differed in how many and which levels were distinguished in this way. It is suggested that this initial strengthening could provide an alternative account for previously observed supralaryngeal declination of consonants. Acoustic duration of the consonants is also affected by prosodic position, and this lengthening is cumulative like linguopalatal contact, but the two measures are only weakly correlated.

Personality correlates of homophobia.

This study explored the relationship between homophobia and several personality traits (empathy, religiosity, and coping style) in the context of respondents' gender and age. The sample consisted of 714 college students who responded to the Homophobia Attitude Scale (HAS) and personality trait scales. Results revealed that women endorsed fewer homophobic attitudes, beliefs, and behaviors than men and that age was negatively correlated with homophobia. Empathic concern and perspective taking were significantly correlated with lower overall homophobic attitudes, less affect discomfort in regard to gays, and less likelihood to abridge the human rights of gays. Religiosity was significantly correlated with more biased beliefs about the origins of homophobia, greater affective discomfort around gays, less endorsement of human rights for gays, and greater homophobia. Use of denial and isolation as coping styles were positively related to homophobia and use of turning against style was negatively correlated.

Env-specific CTL predominate in cats protected from feline immunodeficiency virus infection by vaccination.

Animal models of HIV-1 have a key role to play in elucidation of the cellular mechanisms responsible for protective immunity. Vaccination of domestic cats with whole inactivated feline immunodeficiency virus (FIV) elicits virus-neutralizing Abs and virus-specific CTL in the peripheral blood and lymphoid organs and affords protection from homologous virus challenge. In the present study we confirm the induction of virus-specific CTL following immunization with whole inactivated FIV vaccine and demonstrate that cats are protected for up to 1 yr following vaccination. Long term protection in vaccinated cats correlates with both higher levels of FIV Env-specific CTL in the peripheral blood following vaccination and the presence of FIV Env-specific memory CD8+ CTL in the lymph nodes, which persist for up to 1 yr following challenge in the absence of detectable virus. The CTL responses observed in vaccinated protected cats differ qualitatively from those in FIV-infected cats. The latter cats either do not generate a memory CTL response or exhibit a Gag-specific memory CTL response. These results show that the protective immunity observed in whole inactivated virus-vaccinated cats is associated with the induction of high levels of Env-specific CTL activity.