Pressurised intraperitoneal aerosolised chemotherapy (PIPAC) for gastric cancer with peritoneal metastases: A systematic review by the PIPAC UK collaborative.

INTRODUCTION: Gastric cancer with peritoneal metastases (GCPM) carries a poor prognosis. Pressurised Intraperitoneal Aerosolised Chemotherapy (PIPAC) offers pharmacokinetic advantages over intravenous therapy, resulting in higher chemotherapy concentrations in peritoneal deposits, and potentially reduced systemic absorption/toxicity. This review evaluates efficacy, tolerability and impact on quality of life (QOL) of PIPAC for GCPM. METHODS: Following registration with PROSPERO (CRD42021281500), MEDLINE, EMBASE and The Cochrane Library were searched for PIPAC in patients with peritoneal metastases, in accordance with PRISMA standards RESULTS: Across 18 included reports representing 751 patients with GCPM (4 prospective, 11 retrospective, 3 abstracts, no phase III studies), median overall survival (mOS) was 8 - 19.1 months, 1-year OS 49.8-77.9%, complete response (PRGS1) 0-35% and partial response (PRGS2/3) 0-83.3%. Grade 3 and 4 toxicity was 0.7-25% and 0-4.1% respectively. Three studies assessing QOL reported no significant difference. CONCLUSION: PIPAC may offer promising survival benefits, toxicity, and QOL for GCPM.

Message in a Bottle-Metabarcoding enables biodiversity comparisons across ecoregions.

BACKGROUND: Traditional biomonitoring approaches have delivered a basic understanding of biodiversity, but they cannot support the large-scale assessments required to manage and protect entire ecosystems. This study used DNA metabarcoding to assess spatial and temporal variation in species richness and diversity in arthropod communities from 52 protected areas spanning 3 Canadian ecoregions. RESULTS: This study revealed the presence of 26,263 arthropod species in the 3 ecoregions and indicated that at least another 3,000-5,000 await detection. Results further demonstrate that communities are more similar within than between ecoregions, even after controlling for geographical distance. Overall α-diversity declined from east to west, reflecting a gradient in habitat disturbance. Shifts in species composition were high at every site, with turnover greater than nestedness, suggesting the presence of many transient species. CONCLUSIONS: Differences in species composition among their arthropod communities confirm that ecoregions are a useful synoptic for biogeographic patterns and for structuring conservation efforts. The present results also demonstrate that metabarcoding enables large-scale monitoring of shifts in species composition, making it possible to move beyond the biomass measurements that have been the key metric used in prior efforts to track change in arthropod communities.

The Promise of Proton Beam Therapy for Oesophageal Cancer: A Systematic Review of Dosimetric and Clinical Outcomes.

AIMS: Due to its physical advantages over photon radiotherapy, proton beam therapy (PBT) has the potential to improve outcomes from oesophageal cancer. However, for many tumour sites, high-quality evidence supporting PBT use is limited. We carried out a systematic review of published literature of PBT in oesophageal cancer to ascertain potential benefits of this technology and to gauge the current state-of-the-art. We considered if further evaluation of this technology in oesophageal cancer is desirable. MATERIALS AND METHODS: A systematic literature search of Medline, Embase, Cochrane Library and Web of Science using structured search terms was carried out. Inclusion criteria included non-metastatic cancer, full articles and English language studies only. Articles deliberating technical aspects of PBT planning or delivery were excluded to maintain a clinical focus. Studies were divided into two sections: dosimetric and clinical studies; qualitatively synthesised. RESULTS: In total, 467 records were screened, with 32 included for final qualitative synthesis. This included two prospective studies with the rest based on retrospective data. There was heterogeneity in treatment protocols, including treatment intent (neoadjuvant or definitive), dose, fractionation and chemotherapy used. Compared with photon radiotherapy, PBT seemed to reduce dose to organs at risk, especially lung and heart, although not for all reported parameters. Toxicity outcomes, including postoperative complications, were reduced compared with photon radiotherapy. Survival outcomes were reported to be at least comparable with photon radiotherapy. CONCLUSION: There is a paucity of high-quality evidence supporting PBT use in oesophageal cancer. Wide variation in intent and treatment protocols means that the role and 'gold-standard' treatment protocol are yet to be defined. Current literature suggests significant benefit in terms of toxicity reduction, especially in the postoperative period, with comparable survival outcomes. PBT in oesophageal cancer holds significant promise for improving patient outcomes but requires robust systematic evaluation in prospective studies.

Inhibition of chemokine (C-X-C motif) receptor four (CXCR4) at the fetal-maternal interface during early gestation in sheep: alterations in expression of chemokines, angiogenic factors and their receptors.

Chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), are involved in significant biological processes associated with early pregnancy including increasing trophoblast invasion and stimulating placental vascularization. To further elucidate functions of CXCL12-CXCR4 signaling during early gestation, our objective was to inhibit CXCR4 in vivo using a CXCR4 antagonist, AMD3100. We hypothesized that inhibition of CXCR4 would negatively affect chemokine and angiogenic factor regulation imperative for placental development in sheep. Osmotic pumps containing PBS (control) or AMD3100 (CXCR4 antagonist) were surgically installed ipsilateral to the corpus luteum on d 12 of gestation and administered treatments directly into the uterine lumen. Maternal (caruncle and intercaruncle) and fetal membrane tissues were collected on d 23 of gestation and mRNA and protein expression were analyzed for vascular endothelial growth factor (VEGF), kinase insert domain receptor (KDR), fms related tyrosine kinase 1 (FLT1), fibroblast growth factor 2 (FGF2), angiopoietin 1 (ANGPT1), hypoxia inducible factor 1 ɑ subunit (HIF1A), CXCL12, and its corresponding receptors (CXCR4 and CXCR7). Immunohistochemical procedures were performed for analysis of CXCL12 and cell proliferation. In caruncle tissue ipsilateral to the pump, mRNA for KDR, ANGPT1, HIF1A, and CXCL12 increased (P < 0.05) in treated ewes compared to control, whereas caruncle tissue contralateral to the pump had increased expression (P < 0.05) of KDR, and CXCL12 in treated ewes. In fetal membrane, CXCR4 mRNA and protein decreased (P < 0.05), while VEGF protein decreased (P < 0.05) in caruncle and fetal membrane tissue from treated ewes. Results from this study highlight the importance of CXCL12-CXCR4 signaling at the fetal-maternal interface. Inhibiting this axis may disrupt typical regulation of angiogenic factors needed for placental development and embryo growth.

Quantitative enhancement of speech in noise through a wireless equipped hearing aid.

The development of new hearing aid technology can improve speech understanding in complex listening environments. The purpose of this study is to evaluate the benefit offered by the use of wireless technology applied to hearing aids. Participants were fit with binaural hearing instruments and underwent speech-in-noise tests. The signal was transmitted either by a speaker or wirelessly directly to the hearing aid. In our experience, hearing aids with wireless systems have an advantage in two particular conditions. The first can be achieved while listening wirelessly with microphones excluded (recommended when listening in noisy environments), while the second is in conditions of asymmetric listening; the wireless signal perception remains effective, but at the same time it allows the patient to receive environmental signals. Hearing aids equipped with wireless systems may be particularly useful when listening to people talking even in noisy environments and/ or receiving other sound sources such as TV and landline or cell phones.

Recovery of DNA barcodes from blackfly museum specimens (Diptera: Simuliidae) using primer sets that target a variety of sequence lengths.

In this study, we evaluated the efficacy of various primers for the purpose of DNA barcoding old, pinned museum specimens of blackflies (Diptera: Simuliidae). We analysed 271 pinned specimens representing two genera and at least 36 species. Due to the age of our material, we targeted overlapping DNA fragments ranging in size from 94 to 407 bp. We were able to recover valid sequences from 215 specimens, of which 18% had 500- to 658-bp barcodes, 36% had 201- to 499-bp barcodes and 46% had 65- to 200-bp barcodes. Our study demonstrates the importance of choosing suitable primers when dealing with older specimens and shows that even very short sequences can be diagnostically informative provided that an appropriate gene region is used. Our study also highlights the lack of knowledge surrounding blackfly taxonomy, and we briefly discuss the need for further phylogenetic studies in this socioeconomically important family of insects.

Considerations on the physiopathological mechanism of inner ear damage induced by intravenous cocaine abuse: cues from a case report.

OBJECTIVE: Aim of the following paper is to discuss about the possible etiopathogenetic mechanisms of inner ear damage induced by cocaine abuse. Unfortunately the data concerning this topic are very limited; the authors are then presenting a literature review, also discussing the clinical presentation and the possible therapeutical approach of a clinical case of bilateral sudden sensorineural hearing loss following i.v. injection of cocaine. PATIENTS: Case report. INTERVENTION: A strictly audiological evaluation has been performed, in order to identify the cochlear lesion site(s) and to provide the best medical treatment. CONCLUSIONS: To our knowledge, this is the first report of acute cocaine intoxication with sudden bilateral hearing loss. Further studies are required in order to understand the effects of these substances on the inner ear cells and metabolism.

The McGurk phenomenon in Italian listeners.

In the classic example of the McGurk effect, when subjects see a speaker say /ga/ and hear a simultaneous /ba/, they typically perceive /da/, a syllable that was not presented either acoustically, or visually. This phenomenon, although non-natural and recreated in laboratory investigations, has been studied in order to better understand how, where and when the central nervous system processes and integrates visual and auditory signals. Till now, it has been demonstrated for English, Spanish and German languages, while in Japanese and Chinese it seems weaker. Aim of this study was to evaluate the entity of the McGurk effect for the Italian language. Results obtained demonstrate a robust McGurk effect for the Italian language, which has never been described before. The phenomenon is highly significant when an auditory bilabial Consonant-Vowel is dubbed with a visual apico-dental or velar Consonant-Vowel. Results are discussed on the basis of the recent hypothesis regarding the bimodal perception.

Noise-induced hearing loss: a study on the pharmacological protection in the Sprague Dawley rat with N-acetyl-cysteine.

Noise-induced hearing loss is one of the most common causes of deafness and, at present, there is no treatment for the recovery of the normal hearing threshold after prolonged exposure to loud acoustic stimuli and the generation of acoustic trauma. Prolonged exposure to noise can cause oxidative stress in the cochlea which results in the loss (via apoptotic pathways) of the outer hair cells of the organ of Corti. It has been demonstrated that some antioxidant molecules, for example L-N-acetyl-cysteine, can prevent oxidative stress in the inner ear. Aim of the study was to evaluate whether L-N-acetyl-cysteine, given at various dosages, can preserve the fine structures of the cochlea from the insult of continuous noise. A series of 18 Sprague Dawley male albino rats were exposed to continuous noise (8 kHz octave band noise, 105 dB SPL, 4 hours), and cochlear functionality was evaluated by recordings of transient evoked otoacoustic emissions and distortion products otoacoustic emissions). The group which showed the best protection was that which received a total dosage of 1500 mg/kg of L-N-acetyl-cysteine. These data suggest that while L-Nacetyl-cysteine can partially protect the cochlea from continuous noise, the protection effect is strongly dose-dependent: lower dosages do not fully protect the cochlea and higher dosages can damage the rat systemically (e.g. pulmonary toxicity).

Mobility screening in the elderly and resulting referral.

The aims of this study were to test the usefulness of the Royal College of General Practitioners' (RCGP) mobility screening questionnaire in Irish general practice and to use it to assess the level of mobility problems in the over-75 year old population. Questionnaire screening survey in six faculty areas of the Irish College of General Practitioners(ICGP) well-spread geographically to be representative of the Irish population. Participants were a random sample of 627 people aged 75 years or over, from the General Medical Services list of 92 volunteer general practitioners. The Royal College of General Practitioners' screening questionnaire for mobility was administered by each person's doctor. Suggested interventions were also noted. 92% felt able to get around the house independently, with 78% able to manage stairs independently. The commonest aid to mobility was a stick, used by 27%. Mental impairment was closely associated with inability to get around the house (86% of those not independent around the house scored less than 8 on the Abbreviated Mental Test Score). Analysis of referral patterns indicated possible deficiencies in the availability of physiotherapy in certain areas. The RCGP mobility screening questionnaire was easy to use, and helpful in detecting problems which might require attention.

[Measurements of directional hearing aid function]. / Misure di guadagno funzionale su protesi acustiche direzionali.

A digitally programmable hearing aid, equipped with a directional microphone system, has been tested on 5 subjects suffering from severe sensorineural hearing loss. The hearing aids were individually fitted and two gain response curves-respectively designed for omnidirectional (OD) and directional (D) listening-where chosen and tested. The functional gain, as measured from the speech perception threshold for sentences spoken in a quiet environment, was essentially the same for both settings. The D setting revealed its advantages when listening to a frontal speech source while the background noise of a "cocktail party" was delivered from behind the subjects. The D setting permits better tolerance of background noise with a hearing aid, as demonstrated by the signal-to-noise ratio which, at parity performance (50% correct responses), proved 2 to 5 dB lower than that obtained with the OD setting.

Clinical applicability of transient evoked otoacoustic emissions: identification and classification of hearing loss.

The study aimed at the development of a clinically applicable methodology that could: (1) discriminate transient evoked otoacoustic emission (TEOAE) recordings from normal hearing or hearing impaired individuals; (2) classify the nature of the hearing loss as conductive or as cochlear, and (3) define clear-cut TEOAE clinical criteria. A classification algorithm based on a multivariate discriminant analysis of fast Fourier transform data from recordings evoked by click stimuli of 50 +/- 2, 62 +/- 2, 68 +/- 2 and 80 +/- 2 dB SPL was used to discriminate 302 normal subjects from 383 subjects suffering from mild to moderate hearing losses. The best discriminant model (QDF80) produced a sensitivity of 93.8% and a specificity of 79.4%. When extra correlation criteria were serially applied to the classification outcome, the specificity was increased to 85.3%, but the sensitivity was marginally decreased to 91.7%. The classification of the correctly identified hearing-impaired cases yielded 93.8% identification of conductive and 75.1% identification of cochlear cases. A sensitivity analysis of the misclassified hearing-impaired cases suggested that the TEOAE spectra are well correlated with the 2-kHz but poorly correlated with the 4-kHz octave frequency.

[Loudness scaling for narrow band noise and speech signal]. / Stime categoriche di loudness per rumore a banda stretta e per segnale vocale.

A group of normal-hearing subjects underwent an experimental procedure to obtain estimates of loudness for two narrow band noises, centered at 0.25 and 3 kHz respectively, and meaningful unfiltered speech signals (sentences). Stimuli consisted of 12 intensity levels, spaced equally over the dynamic auditory range. The subjects were asked to associate each level of intensity to one 7 loudness categories. The loudness growth for a noise bands is defined by an exponential function. The loudness growth for the speech signal is better approximated by a linear function. However the mean intensity/loudness function shows two steep portions at the low and high intensities and these are separated by a shallow tract between 55 and 75 dB SPL. The loudness growth for meaningful speech signals--differing from the typical exponential function shown by noise stimuli--seems to confirm the contribution of factors that depend on central auditory organization, most likely operated by the perceptive auditory continuity attributes and the semantic content of the speech signals.

Case-finding incontinence in the over-75s.

BACKGROUND: The under-reporting of incontinence in older persons is well known. However, the general practitioner's (GP's) knowledge of incontinence in this population is less wall documented. AIM: To examine the knowledge of Irish GPs regarding incontinence in patients aged over 75, and to examine the relationship between incontinence and cognitive function in this age group. METHOD: Sixty-four GPs from six faculties of the Irish College of General Practitioners (ICGP), spread geographically over Ireland, administered a questionnaire to 10 of their patients, selected from the General Medical Services list, as part of the ICGP 1993 Care of the Elderly Study. A short test of cognitive function, the AMTS, was administered followed by RCGP (Royal College of General Practitioners) screening questions for incontinence, plus questions with regard to patients' prior reporting of incontinence. GPs were also asked to state their prior knowledge of the incontinence status of the patient and to choose from a list of management options including referral, assigning to a public health nurse, and hospital surgical service. RESULTS: Data were analysed on 527 patients aged over 75 years. Forty-four per cent of persons over 75 years reported having experienced urinary incontinence; 9% reported having experienced faecal incontinence. GPs reported full knowledge of the incontinence status in only 33% of their patients. The effects of low cognitive function, sex, and age on the probability of wetting were analysed using logistic regression modelling. Female sex and low cognitive score increased the likelihood of ever wetting; increasing age increased the likelihood of daily wetting. Poor sensitivities for these models limit their usefulness in clinical practice. CONCLUSION: GPs should have a high index of suspicion for incontinence in persons aged over 75. Thorough history-taking, physical examination, and examinations of therapeutic options for individual cases are recommended.

Audiometric patterns of genetic non-syndromal sensorineural hearing loss.

Sixty-five families with non-syndromal sensorineural hearing loss (NS-SNHL) of genetic aetiology were subtyped according to Gorlin et al. Individual audiogram shapes were also classified in order to detect inter- and intra-familial variations. In 48 families with an Autosomal Dominant (AD) inherited form, 26 exhibited the features of (high-frequency) progressive NS-SNHL, 12 those of mid-frequency NS-SNHL, 5 were affected by congenital low-frequency NS-SNHL; 1 kindred showed a progressive low-frequency pattern and another 1 a unilateral NS-SNHL; only 3 kindreds were affected by severe congenital NS-SNHL. Autosomal Recessive (AR) inherited forms were composed of 9 kindreds with severe congenital NS-SNHL, and 7 with moderate congenital NS-SNHL. One X-linked form was identified. AD- and AR-inherited NS-SNHL differed significantly both in severity of hearing impairment and in audiogram shapes. With few exceptions, in each family classified according to Gorlin, most of the affected subjects shared the same audiogram profile. Intrinsic progression of the disease versus ageing was studied in the larger subtype of individuals with the high-frequency loss. Gorlin's classification still remains the best system to classify NS-SNHL, and can provide a broad base to separate a very heterogeneous group of disorders. Results obtained in gene mapping in single large human families or in homologous gene search could be tested in our families. For some of them, namely those with high frequency progressive and low-frequency NS-SNHL, testing should already be feasible.

Deletion of 24 amino acids from the C-terminus of phosphatidylinositol transfer protein causes loss of phospholipase C-mediated inositol lipid signalling.

Phosphatidylinositol transfer protein alpha (PITPalpha) is a 32 kDa protein of 270 amino acids that is essential for phospholipase C-mediated phosphatidylinositol bisphosphate hydrolysis. In addition, it binds and transfers phosphatidylinositol and phosphatidylcholine between membrane compartments in vitro. Here we have used limited proteolysis of PITPalpha by subtilisin to identify the structural requirements for function. Digestion by subtilisin results in the generation of a number of slightly smaller peptide fragments, the major fragment being identified as a 29 kDa protein. The fragments were resolved by size-exclusion chromatography and were found to be totally inactive in both in vivo PLC reconstitution assays and in vitro phosphatidylinositol transfer assays. N-terminal sequencing and MS of the major 29 kDa fragment shows that cleavage occurs at the C-terminus of PITP at Met246, leading to a deletion of 24 amino acid residues. We conclude that the C-terminus plays an important role in mediating PLC signalling in vivo and lipid transfer in vitro, supporting the notion that lipid transfer may be a facet of PITP function in vivo.

[Auditory temporal discrimination: effects of stimulus duration, inter-stimulus interval, attention]. / Discriminazione uditiva temporale: effetti di durata degli stimoli, intervalli interstimolo, attenzione.

A group of 5 normal hearing subjects were studied to determine their perception of the duration of auditory stimuli applied at constant frequency and intensity. In particular, their ability to discriminate between a pair of stimuli was measured. The minimum perceptible difference in duration was evaluated as the Weber fraction (WF) and was a function of the different stimuli duration (from 200 to 3200 ms) and the different interstimulus intervals (from 20 to 7200 ms). In addition, the interference stemming from two different attention conditions was also tested. The WF tended to increase for the 200,400 ms stimuli while it remained unchanged (at around 0.1) for higher durations. On the other hand, the WF was not affected by the inter-stimulus interval although it increased significantly according to attention interference. While these results confirm that estimates of auditory stimuli use attention controlled mechanisms they also suggest that information regarding duration is a stable perception temporarily residing in the short-term auditory memory and that it is not particularly susceptible to temporal decay.

ARF and PITP restore GTP gamma S-stimulated protein secretion from cytosol-depleted HL60 cells by promoting PIP2 synthesis.

BACKGROUND: In many cell types, including neutrophils and HL60 cells, there is an absolute requirement for a GTP-dependent step to elicit Ca(2+)-regulated secretion. Neutrophils and HL60 cells secrete lysosomal enzymes from azurophilic granules; this secretion is inhibited by 1% ethanol, indicating that phosphatidate (PA) produced by phospholipase D (PLD) activity may be involved. PLD can use primary alcohols in preference to water during the hydrolytic step, generating the corresponding phosphatidylalcohol instead of PA, its normal product. As ARF (ADP-ribosylation factor) proteins regulate PLD activity and are implicated in constitutive vesicular traffic, we have investigated whether ARF is also required for GTP-dependent secretion in HL60 cells. RESULTS: We have used a cell-permeabilization protocol that allows HL60 cells to become refractory to stimulation with GTP gamma S plus 10 microM Ca2+ with regard to secretion and PLD activity. Permeabilization with streptolysin O for 10 minutes permitted the loss of freely diffusable cytosolic proteins, including ARF proteins. Fractions derived from brain cytosol, enriched in ARF proteins, restored secretory function and PLD activity. The major contaminating protein present in these ARF-enriched fractions was identified as phosphatidylinositol transfer protein (PITP). Unexpectedly, PITP was also found to restore GTP gamma S-dependent secretion. Restoration of secretory function was characterized using recombinant proteins, rARF1 and rPITP alpha and rPITP beta. The rARF1 protein restored both secretory function and PLD activity, whereas PITP only restored secretory function. However, both ARF and PITP were capable of stimulating phosphatidylinositol bis phosphate (PIP2) synthesis. CONCLUSIONS: ARF and PITP restore secretory function in cytosol-depleted cells when stimulated with GTP gamma S plus Ca2+. We have previously shown that PITP participates in the synthesis of PIP2. In comparison, ARF1 activates PLD, producing PA, which is a known activator of phosphatidylinositol-4-phosphate 5 kinase, the enzyme responsible for PIP2 synthesis. We propose that ARF and PITP both restore exocytosis by a common mechanism-promoting PIP2 synthesis.

Requirement for phosphatidylinositol transfer protein in epidermal growth factor signaling.

Stimulation of phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis is a widespread mechanism for receptor-mediated signaling in eukaryotes. Cytosolic phosphatidylinositol transfer protein (PITP) is necessary for guanosine triphosphate (GTP)-dependent hydrolysis of PIP2 by phospholipase C-beta (PLC-beta), but the role of PITP is unclear. Stimulation of phospholipase C-gamma (PLC-gamma) in A431 human epidermoid carcinoma cells treated with epidermal growth factor (EGF) required PITP. Stimulation of PI-4 kinase in cells treated with EGF also required PITP. Coprecipitation studies revealed an EGF-dependent association of PITP with the EGF receptor, with PI-4 kinase, and with PLC-gamma.