Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial.

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Hazard Group 3 agent decontamination using hydrogen peroxide vapour in a class III microbiological safety cabinet.

AIMS: This study investigated the efficacy of hydrogen peroxide vapour (HPV) at inactivating hazard group 3 bacteria that have been presented dried from their growth medium to present a realistic challenge. METHODS AND RESULTS: Hydrogen peroxide vapour technology (Bioquell) was used to decontaminate a class III microbiological safety cabinet containing biological indicators (BIs) made by drying standard working suspensions of the following agents: Bacillus anthracis (Ames) spores, Brucella abortus (strain S99), Burkholderia pseudomallei (NCTC 12939), Escherichia coli O157 ST11 (NCTC 12079), Mycobacterium tuberculosis (strain H37Rv) and Yersinia pestis (strain CO92) on stainless steel coupons. Extended cycles were used to expose the agents for 90 min. The HPV cycle completely inactivated B. anthracis spores, B. abortus, B. pseudomallei, E. coli O157 and Y. pestis when BIs were processed using quantitative and qualitative methods. Whilst M. tuberculosis was not completely inactivated, it was reduced by 4 log10 from a starting concentration of 106 colony-forming units. CONCLUSIONS: This study demonstrates that HPV is able to inactivate a range of HG3 agents at high concentrations with associated organic matter, but M. tuberculosis showed increased resistance to the process. SIGNIFICANCE AND IMPACT OF THE STUDY: This publication demonstrates that HPV can inactivate HG3 agents that have an organic load associated with them. It also shows that M. tuberculosis has higher resistance to HPV than other agents. This shows that an appropriate BI to represent the agent of interest should be chosen to demonstrate a decontamination is successful.

Late diagnosis, delayed presentation and late presentation among persons enrolled in a clinical HIV cohort in Ontario, Canada (1999-2013).

OBJECTIVES: Timely HIV diagnosis and presentation to medical care are important for treatment and prevention. Our objective was to measure late diagnosis, delayed presentation and late presentation among individuals in the Ontario HIV Treatment Network Cohort Study (OCS) who were newly diagnosed in Ontario. METHODS: The OCS is a multi-site clinical cohort study of people living with HIV in Ontario, Canada. We measured prevalence of late diagnosis [CD4 count < 350 cells/µL or an AIDS-defining condition (ADC) within 3 months of HIV diagnosis], delayed presentation (≥ 3 months from HIV diagnosis to presentation to care), and late presentation (CD4 count < 350 cells/µL or ADC within 3 months of presentation). We identified characteristics associated with these outcomes and explored their overlap. RESULTS: A total of 1819 OCS participants were newly diagnosed in Ontario from 1999 to 2013. Late diagnosis (53.0%) and presentation (54.0%) were common, and a quarter (23.1%) of participants were delayed presenters. In multivariable models, the participants of delayed presentation decreased over calendar time, but that of late diagnosis/presentation did not. Late diagnosis contributed to the majority (> 87%) of late presentation, and the prevalence of delayed presentation was similar among those diagnosed late versus early (13.4 versus 13.4%, respectively; P = 0.99). Characteristics associated with higher odds of late diagnosis/presentation in multivariable analyses included older age at diagnosis/presentation; African, Caribbean and Black race/ethnicity; Indigenous race/ethnicity; female sex; and being a male who did not report sex with men. There were lower odds of late diagnosis/presentation among participants who had ever injected drugs. In contrast, delayed presentation risk factors included younger age at diagnosis and having ever injected drugs. CONCLUSIONS: Late presentation is common in Ontario, as it is in other high-income countries. Our findings suggest that efforts to reduce late presentation should focus on facilitating earlier diagnosis for the populations identified in this analysis.

Imaging the dome of Santa Maria del Fiore using cosmic rays.

The dome of Santa Maria del Fiore, Florence Cathedral, was built between 1420 and 1436 by architect Filippo Brunelleschi and it is now cracking under its own weight. Engineering efforts are under way to model the dome's structure and reinforce it against further deterioration. According to some scholars, Brunelleschi might have built reinforcement structures into the dome itself; however, the only known reinforcement is a wood chain 7.75 m above the springing of the Cupola. Multiple scattering muon radiography is a non-destructive imaging method that can be used to image the interior of the dome's wall and therefore ascertain the layout and status of any iron substructure in it. A demonstration measurement was performed at the Los Alamos National Laboratory on a mock-up wall to show the feasibility of the work proposed, and a lightweight and modular imaging system is currently under construction. We will discuss here the results of the demonstration measurement and the potential of the proposed technique, describe the imaging system under construction and outline the plans for the measurement.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Testing the level of ant activity associated with quorum sensing: an empirical approach leading to the establishment and test of a null-model (response to the comment of Richardson et al.).

In a paper in this journal (Nouvellet et al., 2010), we presented results from experiments on the behaviour of the Pharaoh's ant, Monomorium pharaonis, along with a substantial statistical and theoretical analysis of the results. In a minor part of our paper, we compared our results with the related work of Richardson et al. (2010a). These authors have subsequently commented on our interpretation of their work (Richardson et al., 2011). In this Letter we respond to the comments of Richardson et al. (2011), and give detailed arguments why we stand by our original conclusions.

SNCA, MAPT, and GSK3B in Parkinson disease: a gene-gene interaction study.

BACKGROUND AND PURPOSE: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene-gene interactions between SNCA, MAPT, and GSK3B in association with PD. METHODS: Three Caucasian PD patient-control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2-discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. RESULTS: Our findings indicate that as previously reported, the SNCA rs356219-G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair-wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219-G and MAPT rs1052553-H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. CONCLUSIONS: In the Caucasian patient-control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.

Testing the level of ant activity associated with quorum sensing: An empirical approach leading to the establishment and test of a null-model.

On the basis of experimental observations, this paper develops two well-defined mathematical models for the level of activity of Pharaoh's ants within their nesting area, with the aim of providing a more general understanding of animal activity. Under specific conditions, we observe that the activity of ants within their nesting area appears to show no dependence on their density. Making the assumption that all ants move independently of one another, this behaviour can be mathematically modelled as a random process based on the binomial distribution. Developing the model on this basis allows an exponential distribution to be exposed that underlies the time-intervals between ants leaving the nesting area. Such a distribution is present, irrespective of whether the ant population in the nesting area remains constant or steadily depletes, and suggests that ant-ant interactions do not play any significant role in determining ant activity under the experimental conditions adopted. The mathematical framework presented plays the role of a null model that will have a wide range of applications for detecting other determinants of activity-level (not addressed in this study) including environmental and social factors such as food availability, temperature, humidity, presence of pheromone trails, along with intraspecific and interspecific interactions outside the nest and, indeed, more generally. The null model should have applications to a range of organisms. Lastly, we discuss our data in relation to a recent study of ants leaving their nest (Richardson et al., 2010) in which the null model was rejected in favour of record dynamics, where ant-ant interactions were conjectured to play a role.

Migraine is comorbid with multiple sclerosis and associated with a more symptomatic MS course.

The objectives of this study were: (1) to assess relative frequency of migraine in multiple sclerosis (MS) patients using the validated self-administered diagnostic questionnaire, and to compare the migraine rates in MS outpatients to age- and gender-matched historical population controls; (2) to compare clinical and radiographic characteristics in MS patients with migraine and headache-free MS patients. We conducted a cross-sectional study to assess the demographic profiles, headache features and clinical characteristics of MS patients attending a MS clinic using a questionnaire based on the American Migraine Prevalence and Prevention (AMPP) study. We compared the relative frequency of migraine in MS clinic patients and AMPP cohort. We also compared clinical and radiographic features in MS patients with migraine to an MS control group without headache. Among 204 MS patients, the relative frequency of migraine was threefold higher than in population controls both for women [55.7 vs. 17.1%; prevalence ratio (PR) =3.26, p<0.001] and men (18.4 vs. 5.6%; PR=3.29, p<0.001). In a series of logistic regression models that controlled for age, gender, disease duration, ß-interferon use, and depression, migraine in MS patients was significantly associated (p<0.01) with trigeminal and occipital neuralgia, facial pain, Lhermitte's sign, temporomandibular joint pain, non-headache pain and a past history of depression. Migraine status was not significantly associated with disability on patient-derived disability steps scale or T2 lesion burden on brain MRI. Migraine is three-times more common in MS clinic patients than in general population. MS-migraine group was more symptomatic than the MS-no headache group.

Potentially Harmful Ionizing Radiation Exposure from Diagnostic Tests and Medical Procedures in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) may have significant potentially harmful ionizing radiation exposure (PHIRE) from diagnostic tests and medical procedures (DTMP) during their initial hospitalization. METHODS: In this single-center, retrospective, observational study, we evaluated the incidence of PHIRE using all patients with radiographically proven aSAH who survived hospitalization over a 6-year period. Patient data were then used to fit a full logistic regression model, a reduced-variable logistic regression model with least absolute shrinkage and selection operator penalty, and a nonparametric tree-based model. Testing data were then used to calculate each predictive model's accuracy. RESULTS: Of 192 patients included in this study, 69 (35.9%) met criteria for PHIRE. Patients with PHIRE were more likely to have a poor Hunt-Hess Score (40.6% vs. 12.2%, P < 0.0001), a poor modified Fischer Grading Scale score (30.4% vs. 16.3%, P = 0.03), ventriculostomy (91.3% vs. 47.2%, P < 0.0001), vasospasm (81.2% vs. 34.1%, P < 0.0001), and ventriculoperitoneal shunt (31.9% vs. 10.6%, P < 0.001). Parametric PHIRE prediction modeling with a full logistic regression model and reduced-logistic regression modeling with least absolute shrinkage and selection operator penalty demonstrated PHIRE prediction accuracy of 67% and 78% accuracy, respectively. Nonparametric tree-based PHIRE modeling demonstrated a prediction accuracy of 58%. CONCLUSIONS: On the basis of our data, PHIRE occurs in approximately 35% of aSAH patients. The reduced-variable logistic regression model had the greatest predictive accuracy for PHIRE. Future studies should validate our findings and predictive models and, if our conclusions hold, further clarification of the risks of PHIRE and methods to reduce PHIRE should be investigated.

Fundamental insights into the random movement of animals from a single distance-related statistic.

Statistical theories of animal movement have often been based on models of random walks, where movements take place in discrete steps and occur at discrete times. The multiplicity of distributions required in these approaches to describe animal movement (i.e., the distributions of angles, discrete steps, and times) have effects that cannot be simply disentangled, and hence they cannot be unambiguously determined. Here we present a mathematical formulation of continuous animal movements. In this new framework, it is shown that a single time-dependent distance statistic, the mean square displacement, which may be directly measured or mathematically modeled, is a central determinant of such random walks and encapsulates key information about the statistical properties of animal movements. The model and methodology presented here not only allow the determination of what were previously viewed as independent aspects of animal movements, such as the distribution of angular changes in direction, but also, because of the new emphasis on the mean square displacement, they may open up a new set of questions concerning animal movement and related phenomena. The results established in this work are directly applied to the foraging behavior of Pharaoh's ants, and very close agreement is found between observation and theory.

A Novel Tool to Guide Reintegration of Anesthesiologists Into Clinical and Academic Work After Concussion.

Concussion is a common form of mild traumatic brain injury that can cause somatic, cognitive, and behavioral impairments lasting days to weeks. There are no published guidelines or recommendations to facilitate the safe and successful reintegration of anesthesiologist clinicians and trainees into clinical and academic work after concussion. We developed a simple 4-phase postconcussion recovery protocol for anesthesiologists who have suffered concussion and describe the successful use of this postconcussion recovery protocol to support reintegration of an Anesthesiology Critical Care Medicine fellow who developed mild concussion during vacation leave.

Double-stranded RNA interference shows that Engrailed controls the synaptic specificity of identified sensory neurons.

The transcription factor Engrailed (En) controls the topography of axonal projections by regulating the expression of cell-adhesion molecules [1] [2] [3] [4] but it is not known whether it also controls the choice of individual synaptic target cells. In the cercal sensory system of the larval cockroach (Periplaneta americana), small numbers of identified wind-sensitive sensory neurons form highly specific synaptic connections with 14 identified giant interneurons [5] [6], and target-cell choice is independent of the pattern of axonal projections [6]. En is a putative positional determinant in the array of cercal sensory neurons [7]. In the present study, double-stranded RNA (dsRNA) interference [8] was used to abolish En expression. This treatment changed the axonal arborisation and synaptic outputs of an identified En-positive sensory neuron so that it came to resemble a nearby En-negative cell, which was itself unaffected. We thus demonstrate directly that En controls synaptic choice, as well as axon projections.

Parameter-free testing of the shape of a probability distribution.

The Kolmogorov-Smirnov test determines the consistency of empirical data with a particular probability distribution. Often, parameters in the distribution are unknown, and have to be estimated from the data. In this case, the Kolmogorov-Smirnov test depends on the form of the particular probability distribution under consideration, even when the estimated parameter-values are used within the distribution. In the present work, we address a less specific problem: to determine the consistency of data with a given functional form of a probability distribution (for example the normal distribution), without enquiring into values of unknown parameters in the distribution. For a wide class of distributions, we present a direct method for determining whether empirical data are consistent with a given functional form of the probability distribution. This utilizes a transformation of the data. If the data are from the class of distributions considered here, the transformation leads to an empirical distribution with no unknown parameters, and hence is susceptible to a standard Kolmogorov-Smirnov test. We give some general analytical results for some of the distributions from the class of distributions considered here. The significance level and power of the tests introduced in this work are estimated from simulations. Some biological applications of the method are given.

Two Drosophila innexins are expressed in overlapping domains and cooperate to form gap-junction channels.

Members of the innexin protein family are structural components of invertebrate gap junctions and are analogous to vertebrate connexins. Here we investigate two Drosophila innexin genes, Dm-inx2 and Dm-inx3 and show that they are expressed in overlapping domains throughout embryogenesis, most notably in epidermal cells bordering each segment. We also explore the gap-junction-forming capabilities of the encoded proteins. In paired Xenopus oocytes, the injection of Dm-inx2 mRNA results in the formation of voltage-sensitive channels in only approximately 40% of cell pairs. In contrast, Dm-Inx3 never forms channels. Crucially, when both mRNAs are coexpressed, functional channels are formed reliably, and the electrophysiological properties of these channels distinguish them from those formed by Dm-Inx2 alone. We relate these in vitro data to in vivo studies. Ectopic expression of Dm-inx2 in vivo has limited effects on the viability of Drosophila, and animals ectopically expressing Dm-inx3 are unaffected. However, ectopic expression of both transcripts together severely reduces viability, presumably because of the formation of inappropriate gap junctions. We conclude that Dm-Inx2 and Dm-Inx3, which are expressed in overlapping domains during embryogenesis, can form oligomeric gap-junction channels.

A study of CR-39 plastic charged-particle detector replacement by consumer imaging sensors.

Consumer imaging sensors (CIS) are examined for real-time charged-particle detection and CR-39 plastic detector replacement. Removing cover glass from CIS is hard if not impossible, in particular for the latest inexpensive webcam models. We show that $10-class CIS are sensitive to MeV and higher energy protons and α-particles by using a 90Sr ß-source with its cover glass in place. Indirect, real-time, high-resolution detection is also feasible when combining CIS with a ZnS:Ag phosphor screen and optics. Noise reduction in CIS is nevertheless important for the indirect approach.

Isotopic characterisation of the historical lead deposition record at Glensaugh, an organic-rich, upland catchment in rural N.E. Scotland.

As part of a wider investigation of the biogeochemistry and fate of Pb deposited from the atmosphere at Glensaugh, a rural upland catchment in N.E. Scotland, the concentration and isotopic composition of Pb were determined in four thinly sectioned monolith cores (25 cm) of peat collected at altitudes of 426--434 m from different faces of Thorter Hill and in a series of 21 10-cm unsectioned cores of peat and organic-rich soil along a transect from near the top (434 m) to the bottom (224 m) of the catchment. Depth profiles of Pb concentration and (206)Pb/(207)Pb ratio were similar for the longer cores. Subsurface Pb maxima (238--489 mg kg(-1)) typically occurred below (206)Pb/(207)Pb minima (1.123-1.134). One core was (210)Pb-dated and had a fairly constant (206)Pb/(207)Pb value of 1.170 from mid-19th century to ca. 1930, followed by a decline (attributable to the increasing influence of Australian Pb of much lower (206)Pb/(207)Pb ratio) to 1.134 by the early 1990s, and then a rapid increase to 1.160 by 2002, after the phased withdrawal of leaded petrol. The fluxes of Pb increased from 15 mg m(-2) year(-1) in the late 19th century to a peak of 60 mg m(-2) year(-1) ca. 1960, before declining steadily to 3.6 mg m(-2) year(-1) by the beginning of the 21st century. Some 40% of the anthropogenic Pb in the core had been deposited prior to 1900. The mean anthropogenic Pb inventory of the four longer cores was 7.4+/-1.5 g m(-2), of which approximately 70% occurred in the top 10 cm, in good agreement with the inventories of the shorter cores collected above 400 m. These inventories are higher than those of the industrial central belt of Scotland, probably because of enhanced deposition at altitude. This is consistent with the derived average (210)Pb flux of 198+/-11 Bq m(-2) year(-1), which is twice that of typical UK (210)Pb deposition and the rainfall for the site. The past deposition of Pb at Glensaugh, including that from sources (e.g., smelting, coal combustion) other than leaded petrol, has clearly been considerable. Even since the introduction of leaded petrol ca. 1930, car-exhaust emissions may have accounted for no more than 35% of the Pb deposited.

Tackling the social and structural drivers of HIV in Canada.

There is new hope that we can significantly reduce HIV rates. The United Nations AIDS organization, UNAIDS, has challenged all countries to strive for aggressive targets that could significantly bend the curve on HIV infections and deaths: 90% of people living with HIV diagnosed; 90% of people diagnosed on treatment; and 90% of people on treatment virally suppressed. This new optimism is largely driven by strong research findings that early and ongoing HIV treatment improves individual health outcomes and reduces people's viral load, making them less infectious. However, the risk of HIV infection is far from evenly distributed among populations most at risk. Those most at risk will find it hardest to reach these targets as they are caught in a syndemic (synergistic epidemic) of intertwining health and social issues. Our research, and that of others, shows that those who are in a syndemic of co-occurring mental health, addiction and social issues (e.g. homelessness, food insecurity) are significantly more likely to fall out of care, less likely to adhere to treatment and less likely to achieve/maintain an undetectable viral load. Intervention studies have found that a combination approach to HIV prevention and treatment that goes beyond primary care and mental health tools to include social and structural interventions has a protective effect, and can reduce risk and improve adherence. People living with and at risk of HIV need better access to social and mental health services as well as clinical treatment services that will help them achieve and maintain optimal health and well-being. We strongly encourage those in the HIV sector across the country to identify a common vision, with clear goals and targets. With concerted and targeted efforts, a focus on program and implementation science, and a willingness to see and treat HIV as a social as well as a biomedical problem-the fourth decade of HIV in Canada could well be the last.

Comparative anatomy of serotonin-like immunoreactive neurons in isopods: putative homologues in several species.

It is now commonly accepted that the arthropod nervous system has evolved only once, and so homologies between crustacean and insect nervous systems can be meaningfully sought. To do this, we have examined the distribution of serotonin (5-hydroxytryptamine)-like immunoreactive neurons in the central nervous system (CNS) of four common British isopods. Two species of terrestrial woodlouse, Oniscus asellus and Armadillidium vulgare, the littoral sea slater, Ligia oceanica, and the aquatic water hoglouse, Asellus meridianus, all possess approximately 40 pairs of serotonin-like immunoreactive neurons, distributed throughout the CNS in a very similar pattern. Interspecific homology is clearly suggested. Serotonin-like immunoreactive neurons in the first (T1) and fourth (T4) thoracic ganglia are particularly prominent in each of the four species studied. Whole-mount immunohistochemistry shows that the pair of T1 neurons have large dorsolateral cell bodies and prominent neurites that project medially and then anteriorly, whereas the pair of T4 neurons have ventrolateral cell bodies and neurites that bifurcate to form a thin axon projecting anteriorly to terminate in T3 and a thick medial axon that projects posteriorly into the abdominal neuromeres of the terminal ganglion. Intracellular cobalt staining of these neurons reveals more of their arborizations: the T1 neurons send three processes anteriorly, which arborize in the brain and exist from the CNS via peripheral nerves, whereas the T4 neurons contribute considerably to the extensive pattern of serotonin-like immunoreactive fibres in T3-T6 ganglia. The overall pattern of serotonin-like immunoreactive neurons in the isopods is similar to that in decapod crustacea, and a number of putative homologies can be assigned. It is more difficult to homologize the isopod serotonin-like immunoreactive neurons with those in the insect CNS, but some stained brain and thoracic neurons share common cell body positions and axon trajectories in isopods, decapods, and insects and may therefore be homologous.

Null mutation in shaking-B eliminates electrical, but not chemical, synapses in the Drosophila giant fiber system: a structural study.

Mutations in the Drosophila shaking-B gene perturb synaptic transmission and dye coupling in the giant fiber escape system. The GAL4 upstream activation sequence system was used to express a neuronal-synaptobrevin-green fluorescent protein (nsyb-GFP) construct in the giant fibers (GFs); nsyb-GFP was localized where the GFs contact the peripherally synapsing interneurons (PSIs) and the tergotrochanteral motorneurons (TTMns). Antibody to Shaking-B protein stained plaquelike structures in the same regions of the GFs, although not all plaques colocalized with nsyb-GFP. Electron microscopy showed that the GF-TTMn and GF-PSI contacts contained many chemical synaptic release sites. These sites were interposed with extensive regions of close membrane apposition (3.25 nm +/- 0.12 separation), with faint cross striations and a single-layered array of 41-nm vesicles on the GF side of the apposition. These contacts appeared similar to rectifying electrical synapses in the crayfish and were eliminated in shaking-B2 mutants. At mutant GF-TTMn and GF-PSI contacts, chemical synapses and small regions of close membrane apposition, more similar to vertebrate gap junctions, were not affected. Gap junctions with more vertebratelike separation of membranes (1.41 nm +/- 0.08) were abundant between peripheral perineurial glial processes; these were unaffected in the mutants.

Correlation of filiform hair position with sensory afferent morphology and synaptic connections in the second instar cockroach.

An attempt is made to relate the distribution of filiform hairs on the cercus of the second instar cockroach, Periplaneta americana, to the morphology and patterns of synaptic connectivity of their afferents. We studied the most distal 25 of the 39 filiform hairs which are commonly present. Filiform afferent arborizations were stained by cobalt filling from the cell body in the cercus. Three fundamental arbor types were found, two similar to those of the first instar medial (M) and lateral (L) afferents, and a third, novel type. L-type arbors could be divided into four subtypes. The most obvious correlate of arbor type is the circumferential position of the hair on the cercus. The proximodistal position of the sensillum within each cercal segment is also a determinant of its arbor. By comparison of hair positions and afferent morphologies, we were able to ascribe homologies between the second instar hairs and members of adult longitudinal hair columns. The patterns of monosynaptic connections between afferents and giant interneurons (GIs) 1, 2, 3, 5, and 6 were determined by recording synaptic potentials in GIs evoked by direct mechanical displacement of individual filiform hairs. Latency from stimulus onset to the rise phase of the first excitatory postsynaptic potential (EPSP) was used as the criterion of monosynapticity. The EPSP amplitudes of the two original L and M afferents are halved in the second instar, in the absence of a significant decrease in GI input resistance. The other afferents can be divided into two basic classes: those which input to GI5 (M-type), and those which input to GI3 and GI6 (L-type). The former is correlated with a central or medial position, while the latter is associated with a group of afferents situated laterally on the cercus. In segments 3 and 4, input to GIs 1 and 2 also correlates with a medial cercal position, however, in the more proximal segments 5 and 6, afferents at all positions input to these interneurons. The occurrence of afferents of identical morphology and similar connectivity in equivalent positions in different segments suggests that each sensory neuron is determined by its two-dimensional position within a segment. The presence of afferents with the same morphology which display proximodistal differences in synaptic connectivity, and of other afferents which have M-type connectivity despite L-type morphology, means that anatomy is generally a poor predictor of synaptic connectivity.