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Biomedical subjects

K Jacobs

Publications and source records attributed to K Jacobs.

At least 37 records · Page 2Linked to original sources
PubMed1998

Spinodal dewetting in liquid crystal and liquid metal films

Theory predicts that dewetting of a homogeneous liquid film from a solid surface may proceed via unstable surface waves on the liquid. This phenomenon, usually termed spinodal dewetting, has been sought after in many systems. Observations in liquid crystal and liquid metal films showed that, as expected, the emerging structures were similar to those found for spinodal decomposition in mixtures. Certain differences, however, could be attributed to peculiarities of the wetting forces in these two dissimilar systems, thereby demonstrating the role of nonlinearities inherent in the wetting forces.

Journal Article↗
PubMed1998

Tracing of a neuronal network in the locust by pressure injection of markers into a synaptic neuropil.

Central neuronal circuits of vertebrates have often been investigated using injection of markers into synaptic neuropils, whereas similar techniques have rarely been applied in invertebrates. In this study we tested several neuroanatomical tracers for their ability to mark central neuronal circuits in insects, using the well described auditory network of the locust, Locusta migratoria. After physiological localization of an auditory neuropil various tracers were pressure injected. Horseradish peroxidase, dextrans (3 and 10 kDa) and especially biocytin and neurobiotin were effectively incorporated by auditory interneurons, which resulted in their extensive labeling. Postsynaptic regions turned out to be the major, if not exclusive sites of uptake of injected markers, which is deduced from two lines of evidence: (i) for labeling of identified auditory neurons it was necessary to apply the tracer to postsynaptic sites of the neuron; (ii) only a few non-auditory neurons were labeled (probably by lesioning axons during electrode impalement). No evidence could be found for an activity dependent uptake. We conclude that pressure injection of certain tracers into synaptic areas can be used to identify central nervous circuits in insects.

Acoustic Stimulation↗
PubMed1998

Inhibitory function in two models of chronic epileptogenesis.

Although drug-induced disinhibition is a potent method for producing acute epileptogenesis, data with respect to possible disorders of GABAergic inhibitory function in models of chronic epilepsy are incomplete and inconsistent. We examined rat models of cortical post-traumatic epilepsy, and epileptogenic cortical microgyri. Results suggest enhanced rather than decreased inhibitory function in cortical networks in these preparations. In brain slices from epileptogenic chronically isolated cortex, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature (m)IPSCs in layer V pyramidal neurons is increased compared to control. In the epileptogenic zone adjacent to the microgyrus, both spontaneous and stimulus-induced IPSCs are larger in amplitude than control, and the frequency of sIPSCs is more dependent upon glutamatergic excitation of interneurons than in control layer V neurons of homotopic cortex. Immunocytochemical studies show that there is enhanced immunoreactivity for several proteins in GABAergic interneurons of chronic cortical isolations, and suggest that there may be sprouting of GABAergic axons in the area of injury. This conclusion is supported by anatomic data showing an approximate doubling of the number of presumed inhibitory synapses on somata of layer V pyramidal neurons. These anatomic findings are consistent with the increased frequency of mIPSCs on these neurons. Inhibition is robust in both of these chronic models of epileptogenesis. Increased inhibitory electrogenesis might be pictured as part of the epileptogenic process, e.g. a mechanism for synchronizing the discharge of pyramidal neurons, or as a compensatory mechanism that might prevent the development of abnormal activities in some cases, or limit the intensity of epileptogenesis in others.

Animals↗
PubMed1998

Glutathione conjugation of trichloroethylene in rats and mice: sex-, species-, and tissue-dependent differences.

Glutathione (GSH) conjugation of trichloroethylene (Tri) to form S-(1,2-dichlorovinyl)glutathione (DCVG) has been implicated in the nephrotoxicity and nephrocarcinogenicity of Tri. Marked sex- and species-dependent differences exist, however, in the susceptibility to Tri-induced renal toxicity, with the male rat being the most susceptible. The present study, therefore, focuses on potential differences in the initial step of the GSH pathway. Rates of DCVG formation were measured in suspensions of isolated renal cortical cells and isolated hepatocytes from male and female Fischer 344 rats and in kidney and liver microsomes and cytosol from male and female Fischer 344 rats and B6C3F1 mice to determine if sex- and species-dependent differences in GSH conjugation correlate with susceptibility to renal toxicity from Tri. Rates of gamma-glutamyltransferase (GGT) with gamma-glutamyl-p-nitroanilide and glycylglycine as substrates and GSH S-transferase (GST) with 1-chloro-2,4-dinitrobenzene as substrate were also measured in liver and kidney subcellular fractions to provide further information on the biochemical basis of susceptibility to Tri. Rates of DCVG formation in rat kidney cells and kidney subcellular fractions were 5- to 20-fold lower than those in rat hepatocytes and liver subcellular fractions. Rates of DCVG formation in kidney cells and subcellular fractions were comparable in male and female rats with the exception of male rat kidney microsomes, where DCVG formation was below the limit of detection, and those in liver cells and subcellular fractions were >3-fold higher in male rats than in female rats. Rates of DCVG formation in mouse kidney subcellular fractions were approximately 10-fold higher than in corresponding fractions from the rat, whereas those in mouse liver subcellular fractions were 4- to 8-fold higher than in corresponding rat tissues, with rates in male mouse liver cytosol and microsomes being modestly higher than in corresponding fractions from female mice. GGT activity was barely detectable in livers, was about 20-fold higher in rat kidneys than in mouse kidneys, and was slightly higher in female rat kidneys than in male rat kidneys. GST activity with 1-chloro-2,4-dinitrobenzene as substrate exhibited tissue-, sex-, and species-dependent patterns that were generally similar to those with Tri as the substrate. These results suggest that the higher susceptibility to Tri-induced renal toxicity of male rats as compared with female rats correlates with rates of DCVG formation. The high rates of DCVG formation in mice, however, indicate that other factors, possibly including differences in activities of cysteine conjugate beta-lyase or N-acetyltransferase, may also be important determinants of the susceptibility to Tri.

Animals↗
PubMed1997

Lectin histochemistry of the metathoracic ganglion of the locust Schistocerca gregaria before and after axotomy of the tympanal nerve.

The thoracic ganglia of insects exhibit a highly ordered organization. It seems possible that the information underlying the emergence of this order during development and its maintenance throughout insect life is given via a distinct pattern of molecules distributed within the ganglion. The question we asked was whether the adult insect ganglion is subdivided by the distribution of specific carbohydrates and furthermore whether or not this distribution changes during degeneration and regeneration of neurons. In order to determine the normal carbohydrate distribution, we stained sections of the intact metathoracic ganglion of the locust Schistocerca gregaria with fluorescence-coupled lectins. We succeeded in labeling three sensory neuropil areas with either peanut agglutinin (PNA): Phaseolus vulgaris erythrolectin (PVE), soybean agglutinin, wheat germ agglutinin (WGA), or Vicia villosa agglutinin. Apart from this, PNA, WGA, and succinylated WGA also selectively labeled some neuronal cell bodies, including dorsal unpaired median neurons. Datura stramonium lectin (DSL), Griffonia simplicifolia lectin II, and Solanum tuberosum lectin (STL) bound to glial cells or glia surrounding extracellular matrix. A few lectins stained all structures within the ganglion; some showed no binding at all. In the second part of our study, we tested whether carbohydrates were differentially regulated during transient deafferentation after the axotomy of the tympanal nerve. Binding of PNA and PVE within the auditory neuropil did not change. However, binding of the two glia-associated markers, DSL and STL, clearly differed from that found in intact animals; they bound transiently (day 3-4 until day 10-20 post-surgery) to axonal tracts and neuropils of the axotomized sensory afferents.

Afferent Pathways↗
PubMed1997

Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.

We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.

Animals↗
PubMed1997

The insulin gene region and susceptibility to insulin-dependent diabetes mellitus in four races; new insights from Afro-Caribbean race-specific haplotypes.

The IDDM2 component of the genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) has been mapped to chromosome 11p15.5. The exact identity of IDDM2 remains uncertain. It has been suggested that IDDM2 maps within the 5' VNTR (variable number tandem repeat) polymorphism upstream of the insulin gene (INS). This has not been confirmed and a contribution from other INS gene region polymorphisms cannot be excluded. We present INS region genotype data from four racial groups: the Japanese, Hong Kong Chinese, North Indian Asians and Afro-Caribbeans (two groups; one born and resident in the UK, one in Jamaica). These races have not been previously studied with the range of INS region polymorphisms included here. No INS polymorphism was associated with IDDM across all races. These data from this study thus do not identify any INS polymorphism as IDDM2. The Afro-Caribbean race showed a very different distribution of INS genotypes from the other races and novel race-specific INS haplotypes were identified. Analysis of these excluded a contribution to susceptibility to IDDM from the- 23HphI INS polymorphism. An Afro-Caribbean INS haplotype which differed only at the VNTR from the very protective INS haplotype (VPH) identified in white Caucasians was detected. Population analysis of this haplotype will allow direct assessment of the role of the VNTR in susceptibility to IDDM. In conclusion, the diverse Afro-Caribbean TH/INS/IGF2 haplotypes identified in this study will be valuable in mapping IDDM2 more precisely.

Diabetes Mellitus, Type 1↗
PubMed1996

Preparation and structure-activity relationship of novel P1/P1'-substituted cyclic urea-based human immunodeficiency virus type-1 protease inhibitors.

A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

Azepines↗
PubMed1996

Moderate peripheral neuropathy impairs weight transfer and unipedal balance in the elderly.

OBJECTIVE: To quantitatively assess the performance of elderly with and without moderate, electrodiagnostically confirmed peripheral neuropathy (PN) on tasks of weight shifting and maintenance of unipedal balance. PATIENTS AND METHODS: A case control study with PN subjects selected from a computerized data bank of all patients who had undergone electrodiagnostic studies at a university-based referral center. Control subjects of similar age and same gender were selected from the same source. Clinical examination included neurological and gross motor components. Quantitative evaluation included testing while the subjects stood with a force plate under each foot. Center of reaction (CR) excursions and ground reaction forces were quantified in: (1) six trials as subjects transferred their weight from bipedal stance to unipedal stance, on command, and attempted to maintain it for at least 3 seconds; and (2) in two additional trials in which subjects held unipedal stance for as long as possible. RESULTS: No subjects in either group had difficulty with level gait, a 180-degree turn, or required examiner assistance during an eyes-closed Romberg test. Biomechanical testing revealed that although the PN group used the same time to transfer their weight onto one foot as the C group, they achieved a significantly (1) lower rate of success in reliably maintaining 3 seconds of unipedal stance (.12 vs .58, p = .021), and (2) shorter mean maximum unipedal stance time (3.8 vs 32.3sec, p < .001). Furthermore, the PN group experienced greater difficulty in maintaining unipedal stance, as evidenced by significantly greater fluctuations in their ground reaction forces. CONCLUSIONS: The demonstrated impairment in reliability of unipedal stance in elderly with PN likely contributes to their known high rate of falls. Furthermore, unipedal stance testing serves to sharpen the physical examination by verifying the functional significance of impaired distal sensation-a common finding in the elderly.

Aged↗
PubMed1996

The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry.

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ-specific autoimmune disease.

Abatacept↗
PubMed1996

The corporatization of health care: an evaluation and an alternative.

The corporatization of health care organizations has become a significant international trend. This paper examines that trend, comparing the development of corporate health care in the USA with the impact of the New Zealand health reforms. The paper traces the evolution of the organizations of health care systems and explains the emergence of the corporate form. We argue that the corporate model of work organization is unsuited to the complex and ambiguous nature of the medical task as it ignores inherent interdependencies. An alternative is needed which addresses work practices rather than just participation in decision making and is based on a concept of mutual interdependence and support in the execution of work.

Employment↗
PubMed1996

The stroke syndrome of cortical vein thrombosis.

Cortical vein thrombosis without sinus involvement is rarely diagnosed, although it may commonly be overlooked. We report four cases of cerebral venous thrombosis limited to the cortical veins. The diagnosis was made on surgical intervention in one patient and by angiography in three patients. Together with a survey of the published cases, the clinical and neuroimaging patterns of our patients allow delineation of several features suggestive of cortical venous stroke. Focal or generalized seizures followed by hemiparesis, aphasia, hemianopia, or other focal neurologic dysfunction in the absence of signs of increased intracranial pressure should suggest this possibility. Neuroimaging (CT, MRI) shows an ischemic lesion that does not follow the boundary of arterial territories and often has a hemorrhagic component, without signs of venous sinus thrombosis. Conventional angiography demonstrates no arterial occlusion but may show cortical vein thrombosis corresponding to the infarct, although these may also be nonspecific findings. The role of MR angiography, which is well-established in sinus thrombosis, remains to be assessed in patients with brain ischemia due to isolated cortical vein occlusion.

Adult↗
PubMed1995

Isometric cervical extension strength of recreational and experienced cyclists.

The effect for cyclists of the typical forward sitting position on neck strength and its possible relationship to neck pain have not been examined. The purpose of this study was to measure the peak isometric cervical extension strength (PICES) of both recreational and experienced road cyclists and to compare these values to those of noncyclists. Subjects, 45 men between the ages of 18 and 40, were tested for voluntary PICES through a 126 degrees range of motion on a MedX cervical extension machine. No significant differences were found between the three groups in PICES at any angle. When expressed relative to body weight, significant differences in PICES were found at 126 degrees between the control group and the recreational cyclist group (p < 0.05), and between the control group and the experienced cyclist group (p < 0.01), but not at any other angle. Furthermore, no significant differences in strength were found between cyclists experiencing neck pain and those who did not. These data indicate that the cervical muscles of cyclists have not adapted by increasing maximal isometric strength above that of noncyclists, and that the neck pain frequently reported may be due to fatigue from sustained muscular contractions associated with time spent cycling, rather than from muscle weakness.

Adolescent↗
PubMed1994

The hypE gene completes the gene cluster for H2-oxidation in Azotobacter vinelandii.

The nucleotide sequence was obtained for the hypE gene in the cluster of structural and accessory genes required for the assembly and functioning of the membrane-bound, dimeric, (NiFe)hydrogenase in Azotobacter vinelandii. The hypE gene encodes a polypeptide of 341 amino acid residues which is rich in alanine, glycine, valine and proline and appears to be involved in maturation of the enzyme because chromosomal mutations in hypE block O2-dependent H2-oxidation and affect the amount, processing and localization of the (NiFe) hydrogenase alpha-subunit. The complete nucleotide sequence for the hydrogenase gene cluster in A. vinelandii has now been assembled into a contiguous sequence of 13,914 bp containing 16 potential genes which appear to be transcribed undirectionally. They are arranged in the order hoxK, hoxG, hoxZ, hoxM, hoxL, hoxO, hoxQ, hoxR, hoxT, hoxV, hypA, hypB, hypF, hypC, hypD and hypE. This cluster closely resembles those described for comparable (NiFe) hydrogenases in other bacteria.

Amino Acid Sequence↗
PubMed1994

Human dento-gnathic metric variation in mesolithic/neolithic Ukraine: possible evidence of demic diffusion in the Dnieper Rapids region.

Dental and gnathic metrics from a series of Mesolithic and Neolithic cemetery samples in the Dnieper River valley (Ukraine) are compared. Both male and female Neolithic samples have larger dental dimensions, wider dental arcades, and a more robust mandibular corpus than do the Mesolithic samples. In addition, the relative variances (RVs) of bucco-lingual dental breadths (as measured by modified Levene's Tests) show an intriguing pattern of change from the Mesolithic into and through the Neolithic. Female RVs show a clear tenency to increase through time, while male RVs show more mixed tendencies. Such a pattern indicates that the increases in Ukrainian Neolithic dento-gnathic dimensions are plausibly attributable to low intensity gene flow (demic diffusion). Seen in the light of new chronometric, paleodietary, and paleolinguistic information, as well as in the context of recent archaeological models for agro-pastoralist origins in the North Pontic, these data suggest that gene flow via population interactions originating in or transient through the circum-Caucasus may have played an important role in producing the Ukrainian Neolithic dental increase.

Anthropology, Physical↗