Single-column thalamocortical network model exhibiting gamma oscillations, sleep spindles, and epileptogenic bursts

To better understand population phenomena in thalamocortical neuronal ensembles, we have constructed a preliminary network model with 3,560 multicompartment neurons (containing soma, branching dendrites, and a portion of axon). Types of neurons included superficial pyramids (with regular spiking [RS] and fast rhythmic bursting [FRB] firing behaviors); RS spiny stellates; fast spiking (FS) interneurons, with basket-type and axoaxonic types of connectivity, and located in superficial and deep cortical layers; low threshold spiking (LTS) interneurons, which contacted principal cell dendrites; deep pyramids, which could have RS or intrinsic bursting (IB) firing behaviors, and endowed either with nontufted apical dendrites or with long tufted apical dendrites; thalamocortical relay (TCR) cells; and nucleus reticularis (nRT) cells. To the extent possible, both electrophysiology and synaptic connectivity were based on published data, although many arbitrary choices were necessary. In addition to synaptic connectivity (by AMPA/kainate, NMDA, and GABA(A) receptors), we also included electrical coupling between dendrites of interneurons, nRT cells, and TCR cells, and--in various combinations--electrical coupling between the proximal axons of certain cortical principal neurons. Our network model replicates several observed population phenomena, including 1) persistent gamma oscillations; 2) thalamocortical sleep spindles; 3) series of synchronized population bursts, resembling electrographic seizures; 4) isolated double population bursts with superimposed very fast oscillations (>100 Hz, "VFO"); 5) spike-wave, polyspike-wave, and fast runs (about 10 Hz). We show that epileptiform bursts, including double and multiple bursts, containing VFO occur in rat auditory cortex in vitro, in the presence of kainate, when both GABA(A) and GABA(B) receptors are blocked. Electrical coupling between axons appears necessary (as reported previously) for persistent gamma and additionally plays a role in the detailed shaping of epileptogenic events. The degree of recurrent synaptic excitation between spiny stellate cells, and their tendency to fire throughout multiple bursts, also appears critical in shaping epileptogenic events.     

Germline mutations of the CDKN2 gene in UK melanoma families

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.      

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

A method for modulation transfer function determination from edge profiles with correction for finite-element differentiation

In this paper we describe a technique for determining the modulation transfer function (MTF) of an imaging system from an experimentally obtained edge profile. The technique includes an exact correction for the frequency passband of the finite-element differentiation required to obtain the line spread function from the edge spread function. This correction has been ignored by investigators in the past and is required whenever finite-element differentiation is used rather than analytic differentiation of a model fitted to the edge response data. The magnitude of the MTF correction is approximately 11% at f = fc/2 and approximately 57% at f = fc, where fc = fs/2 is the maximum frequency reproducible without aliasing with a sampling rate of fs. The correction is performed in the spatial frequency domain by multiplying the uncorrected MTF by 1/sinc (pi f/2fc). A computer simulation is presented to demonstrate the effect and the correction procedure. An experimental MTF of an x-ray image intensifier system obtained using this technique is found to be consistent with an MTF obtained using a bar pattern test phantom.     

Naturally occurring double-stranded RNA and immune responses. III. Immunogenicity and antigenicity in animals.

Naturally occurring, double-stranded RNA (ds-RNA)) was immunogenic when injected into mice, rats, guinea-pigs, rabbits, dogs and baboons. The response to native material administered intravenously (i.v.) was strongest in rabbits and mice, and weakest in baboons. Mice, guinea-pigs and baboons injected with ds-RNA complexed with methylated BSA emulsified in Freund's complete adjuvant all gave high antibody responses. When ds-RNA was given in aerosol form to mice and guinea-pigs the response was weaker than that following i.v. injection, and baboons did not respond to antigen given as an aerosol. In most species the immune response obtained was predominantly IgM in nature, and there was no evidence for cell-mediated immunity in any species. The only evidence of an adverse reaction associated with repeated administration of ds-RNA was a systemic anaphylactic-type response in a small group of mice given ds-RNA repeatedly in aerosol form and challenged with ds-RNA i.v.     

RecurrentStreptococcus pneumoniae endocarditis

A case of recurrent endocarditis due toStreptococcus pneumoniae, a rare cause of endocarditis, is reported. The first episode of infection resulted in valvular damage, necessitating replacement of the aortic and mitral valves, and the second episode was treated successfully with antibiotics alone. Recurrence occurred even though the organism was fully susceptible to the antibiotics used and the patient showed no evidence of immune deficiency.     

Requirement for matching T cell and B cell subsets in secondary anti-hapten antibody responses.

The in vitro secondary anti-hapten response to trinitrophenylated keyhole limpet hemocyanin (TNP-KLH) has been investigated using B and T cells from the same or a pool of identically primed syngeneic individuals. The optimum antibody response obtained from B cells of any given animal was seen when the same individual's T cells were used as a helper cell source. This individual preference was lost if secondary challenge in culture was made with TNP on a heterologous carrier, with the helper cells obtained from suitably primed individuals or a pool thereof. These data are interpreted in terms of a network theory for the regulation of immune responses under physiological conditions.     

The development of a computer controlled system to simulate in rats, the rapid, frequent changes in oxygen experienced by preterm infants developing retinopathy of prematurity

Preterm infants that develop severe ROP have significantly more fluctuations in their transcutaneous oxygen compared to mild or no ROP, despite the fact that all these infants are kept within clinically 'safe' limits. Current animal models do not accurately reflect this oxygen environment. Our aim was to custom build equipment capable of reproducing the transcutaneous oxygen (TcPO2) levels recorded by infant cotside monitoring equipment in a rat model and assess the equipment's precision. Using previously published data for the rat that translates TcPO2 into the equivalent inspired FiO2, a profile was derived from a datalog of TcPO2 values recorded every minute for 14 days in an infant that had developed severe ROP. This profile was controlled in the animal chamber by software algorithms which calculated the amount and type of gas to be injected to move oxygen to each new set-point. CO2 regulation within the chamber was also possible. Absolute differences between the datalog set-points (n = 17,465) and the oxygen sensor were median 0.3% oxygen, IQR 0.2-0.7% oxygen, with 95% of the differences < +/- 2% oxygen. The equipment is capable of reproducing the oxygen environment experienced by a preterm ventilated infant, giving a satisfactory level of precision.     

Screening for cervical cancer in HIV-infected women receiving care in the United States

OBJECTIVE: We examined the sociodemographic, clinical and provider factors associated with screening for cervical cancer among HIV-infected women. METHODS: We studied a national sample representing 43,490 women receiving treatment of HIV infection who completed first follow-up surveys of the HIV Cost and Service Utilization Study (HCSUS). All women were asked, "In the past 12 months, have you had a Pap test?" Women reporting an abnormal Pap test result were asked whether they had been told antibiotics could cure abnormal cells, and whether they were scheduled for another Pap test or for a colposcopy within 3 months. RESULTS: Of the population represented, 81% had had a Pap test in the past 12 months. Women who reported having a gynecologist and primary care physician at the same clinical site were almost twice as likely (odds ratio, 1.9; 95% confidence interval, 1.3-3.0) as other women to report Pap testing. Among women who reported abnormal Pap test results and were not told antibiotics could cure abnormal cells, 95% were scheduled for a repeat Pap test or colposcopy, but 15% of the women had not received their repeat Pap test or colposcopy. CONCLUSION: Although Pap test rates and appropriate referral for abnormal findings were high among HIV-tested women, many women with initially abnormal Pap test results did not actually receive follow-up Pap testing or colposcopy. Providing gynecologic care at the same site as primary HIV care would likely improve delivery of needed gynecologic care for women.     

Ontogeny of the antibody-forming cell line in mice. III. The generation of mature anti-sheep red blood cell-specific B cells is antigen-dependent.

A role for antigen in the generation of fully mature splenic type B cells has been shown. In adoptive transfer experiments, cells from bone marrow or fetal liver required a longer period to give an anti-sheep red blood cell plaque-forming cell (PFC) response than those from spleen. This delay was not overcome by allowing the cells a 7-day sojourn in the irradiated host before antigen challenge. A two-stage protocol was designed in which the in vivo generation of fully mature cells could be measured by their ability to give PFC in lipopolysaccharide-stimulated cultures in vitro. These experiments showed that a critical factor which influences the final differentiation of bone marrow or fetal liver cells into mature, splenic type B cells is exposure to antigen.