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Tensile, room-temperature creep, and fatigue tests were conducted to determine the stability of the mechanical properties of electrodeposited films and to establish a unique strategy to reduce variation in micromachined devices made from them. Microcrystalline nickel films with columnar grains with a typical diameter of less than 1 μm and nanocrystalline films with 20-nm equiaxed grains were evaluated. While the tensile strengths of the films were higher than bulk forms of the material, the strength, strain to failure, and apparent elastic modulus were highly variable. Creep tests revealed that the films accumulated plastic strain rapidly at room temperature and that the apparent elastic modulus increased after exposure to stress. However, the response of the film was sensitive to the local deposition conditions. Fortunately, incremental-step fatigue tests demonstrated that the films cyclically hardened and that further changes in the elastic and plastic deformation responses do not occur after cyclic stabilization. As a result, cyclic stress strain curves and the transient stabilization behavior can be used to define a mechanical “burn-in” sequence for electrodeposited nickel films that will improve the stability and reproducibility of micromachined devices.

Background Mechanical hyperalgesia and allodynia associated with chemical irritant application are mediated by spinal high-threshold (HT) as well as wide-dynamic-range neurons as a result of "central sensitization." Because the pathophysiology of pain is thought to differ depending on the type of injury and may vary between hairy and glabrous skin, the authors examined changes in properties of spinal dorsal horn neurons after surgical incisions in hairy skin of rats to obtain insights into the mechanisms of postoperative pain. Methods Withdrawal responses to punctate mechanical stimulation and gentle brushing were measured in awake rats in an area adjacent to the injured site (primary area) and in an area 2 cm from the injured site (secondary area) after 1-cm longitudinal incisions through the hairy skin, fascia, and muscle had been made in the hindquarters. In a separate study, responses of spinal wide-dynamic-range, HT, and low-threshold neurons to nonnoxious and noxious stimuli were recorded before and after similar incisions had been made in the centers of their receptive fields. Effects of spinal application of the gamma-aminobutyric acid A receptor antagonist bicuculline (15 microg) on responses of HT neurons were then studied. Results Awake rats showed primary and secondary hyperalgesia to punctate mechanical stimulation 30 min after the incision and thereafter for 4 days and 1 day, respectively. Mechanical allodynia associated with brush stimulation was only seen in the primary area 30 min after the incision and thereafter for 1 day. The incision resulted in increases in activity of wide-dynamic-range neurons (receptive field sizes and responses to both innocuous and noxious stimuli). HT neurons did not respond to innocuous stimulation and showed very small increases or no changes in receptive field size and responses to noxious stimuli after the incision. However, the majority of HT neurons began to respond to innocuous stimuli after application of bicuculline (15 microg/50 microl) to the spinal cord. Conclusions The results suggest that wide-dynamic-range neurons are responsible for behavioral hyperexcitability after surgical incision but that HT neurons are not involved in the hyperexcitability, despite the fact that HT neurons are capable of responding to innocuous stimuli by reversal of gamma-aminobutyric acid-mediated inhibition.

Background A major effect of general anesthesia is lack of response in the presence of a noxious stimulus. Anesthetic depression of spinal sensory neuronal responses to noxious stimuli is likely to contribute to that essential general anesthetic action. The authors tested the hypothesis that gamma-aminobutyric acid receptor type A (GABA(A)) and strychnine-sensitive glycine receptor systems mediate halothane depression of spinal sensory neuronal responses to noxious stimuli. Methods Extracellular activity of single spinal dorsal horn wide dynamic range (WDR) neurons was recorded in decerebrate, spinal cord transected rats. Neuronal responses to noxious (thermal and mechanical) and nonnoxious stimuli were examined in the drug-free state. Subsequently, cumulative doses (0.1-2.0 mg/kg) of bicuculline (GABA(A) antagonist) or strychnine (glycine antagonist) were administered intravenously in the absence or presence of 1 minimum alveolar concentration (MAC) of halothane. Results Halothane, 1.1%, depressed the response of WDR neurons to both forms of noxious stimuli. Antagonists, by themselves, had no effect on noxiously evoked activity. However, bicuculline and strychnine (maximum cumulative dose, 2.0 mg/kg) partially but significantly reversed the halothane depression of noxiously evoked activity. Similar results were seen with most, but not all, forms of nonnoxiously evoked activity. In the absence of halothane, strychnine significantly increased neuronal responses to low threshold receptive field brushing. Conclusion Halothane depression of spinal WDR neuronal responses to noxious and most nonnoxious stimuli is mediated, in part, by GABA(A) and strychnine-sensitive glycine systems. A spinal source of glycine tonically inhibits some forms of low threshold input to WDR neurons.

The effects of spinally administered R(−)N6-(2-phenylisopropyl) adenosine (R-PIA) on spinal dorsal horn neurons were investigated in anesthetized rats. Extracellular, single-unit recordings were measured during noxious heating of receptive fields on the hind paw. Three series of experiments were carried out to characterize the effects of R-PIA on spinal dorsal horn neuronal activity. In the first set of experiments, R-PIA dose-dependently suppressed noxiously evoked activity of spinal dorsal horn neurons. In the second set of experiments, R-PIA suppressed noxiously evoked activity in neurons sensitized by the topical application of mustard oil to a region of skin adjacent to their receptive fields. In the third set of experiments, R-PIA prevented mustard oil induced sensitization of dorsal horn neurons. In all cases, the adenosine receptor antagonist theophylline reversed the action of R-PIA. The results of these investigations indicate the involvement of spinal adenosine receptors in spinal pathways of central sensitization and in the modulation of somatically induced noxious pain.

We examined whether the proteinase-activated receptor-2 (PAR2) agonist, H-Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL-NH2), could induce scratching behavior in mice. Intradermal injections of SLIGRL-NH2 (10-50 microg) evoked dose dependent scratching. This behavior peaked near 5 min and returned to preinjection levels within 30 min. Pretreatment of animals with a histamine H1 receptor antagonist, pyrilamine, blocked histamine induced scratching, but it had little effect on SLIGRL scratching. Our study suggests that PAR2 mediates histamine independent itch.

Visceral pain, especially that associated with inflammation of visceral organs, is poorly understood and difficult to treat clinically. The purpose of this study was to investigate the effects of intrathecal 2-amino-5-phosphonovaleric acid (AP5, a competitive NMDA antagonist) upon a visceromotor response to distension of colonic tissue inflamed by exposure to turpentine. All experiments were conducted under pentobarbital anesthesia. Animals were prepared with a laminectomy from T12 to L1 to facilitate intrathecal drug administration. Colonic distension thresholds for a visceromotor response were determined in the presence and absence of AP5. Animals were divided into two groups. The NS group received 50 microl of saline intrathecally and the AP5 group 10 mM of AP5 in 50 microl saline. After baseline measurements, intrathecal drugs were administered. Five minutes later, the effects of intrathecal drugs were measured, then 1 ml of 25% turpentine was administered anorectally. Subsequent measurements were made every 5 minutes for the next 90 minutes. Visceromotor thresholds to colorectal distension (CRD) were significantly decreased 50 min after turpentine administration in the NS group. There was no threshold change in the AP5 group. This study suggests that the administration of the competitive NMDA receptor antagonist AP5 in this model blocks the effect of turpentine sensitization on visceromotor response to CRD. The absence of AP5 effects in animals not sensitized by turpentine suggests that NMDA systems may be involved in the sensitization.

The gingival crevicular fluid (GCF) and monocytic secretion of prostaglandin E2 (PGE2) and interleukin 1 beta (IL-1 beta) were measured in a group of 39 insulin-dependent diabetes mellitus (IDDM) patients and 64 systemically healthy individuals. Diabetics were divided into Group A (gingivitis or mild periodontal disease) and Group B (moderate or severe periodontal disease). Diabetics had significantly higher GCF levels of both PGE2 and IL-1 beta as compared to non-diabetic controls who were matched with regard to periodontal disease severity (P0.00001 and P = 0.0005, respectively). Within the diabetic population, the GCF levels of these inflammatory mediators were almost 2-fold higher in Group B as compared to Group A (P = 0.01, P = 0.006, respectively for GCF-PGE2 and IL-1 beta). Furthermore, diabetics as a group had a significantly higher monocytic PGE2 and IL-1 beta production in response to various concentrations of both Escherichia coli and Prophyromonas gingivalis lipopolysaccharide (LPS) as compared to non-diabetic patients with adult periodontitis (P = 0.0001). LPS dose-response curves demonstrated that monocytes from Group B diabetics produced approximately 3 times more PGE2 than Group A monocytes; however, there was no significant difference in monocytic IL-1 beta secretion within the IDDM patients. The levels of GCF or monocytic mediators did not correlate with age, race, or glycosylated hemoglobin (HbA1C) levels. Our data suggest that the high GCF and monocytic secretion of PGE2 and IL-1 beta in IDDM patients may be a consequence of a systemic response trait and that the presence of Gram-negative infections such as periodontal diseases may interact synergistically to yield high local levels of these mediators and a more severe periodontal condition.

The aim of the present study was to identify whether monocytic TNF alpha secretion patterns could serve as a potential phenotypic discriminator for periodontal disease susceptibility within insulin-dependent diabetes mellitus (IDDM) patients. In 32 IDDM individuals the lipopolysaccharide (LPS) stimulated monocytic TNF alpha secretion dose-response characteristics were analyzed and related to two different periodontal status categories. Diabetics were divided into group A (gingivitis or mild periodontal disease) and group B (moderate to severe periodontal disease). In addition, 17 non-diabetic individuals with various degrees of periodontal disease served as control patients. Diabetics as a group had a significantly higher monocytic TNF alpha production in response to increasing Porphyromonas gingivalis A 7436 lipopolysaccharide concentrations (0, 0.003, 0.03, 0.3 and 3.0 micrograms/ml) as compared to non-diabetic patients with gingivitis or adult periodontitis (p < 0.05). A significant difference in the dose response was also noted in the level of TNF alpha secreted as a function of P. gingivalis LPS concentrations between group A and B diabetics, as determined by two-way repeated measurements ANOVA (p < 0.05). Furthermore, there was no significant difference in the mean HbA1C between the two diabetic groups, and the TNF alpha level was not significantly associated with the HbA1C level within diabetic patients. These data suggest that the diabetic state results in an upregulated monocytic TNF alpha secretion phenotype (4.6-fold increase) which, in the presence of Gram-negative bacterial challenge, is associated with a more severe periodontal disease expression. In addition, approximately 40% (10 of 24) IDDM periodontitis patients in group B demonstrated a 62-fold elevation in TNF alpha secretion relative to non-diabetic gingivitis or periodontitis patients and a 13.5-fold increase relative to IDDM group A (gingivitis or mild periodontitis) patients.

Ketoprofen creams were evaluated for the treatment of periodontal disease in a placebo-controlled, double-blind study in the rhesus monkeys, Macaca mulatta. Two formulations containing ketoprofen (1%), with or without vitamin E, were evaluated against appropriate controls (8 monkeys per group). Two weeks prior to treatment, the animals received prophylaxis on only the left side of the mouth (spontaneous model). Selected teeth on the right side of the mouth were ligated (ligature model). The creams were administered to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months. Clinical assessments were made 2 wk before initiation, at baseline and 1, 2, 3 and 6 months post-treatment. The clinical parameters included plaque formation, gingival redness, edema, bleeding on probing and Ramfjord Attachment Level measurements (RAL). Radiographs were taken at 2 wk before initiation, baseline and at 3 and 6 months post-treatment. Digital, subtraction radiography was used to measure vertical linear bone loss along the interproximal root surfaces of the left and right mandibular first molars. Gingival crevicular fluid (GCF) was collected for biochemical assays on PGE2, TxB2, LTB4, IL-1 beta and TNF alpha. There were no significant differences among groups with respect to gingival indices. Radiographic data demonstrated significant positive effects on bone activity in both groups treated with ketoprofen formulations with improvement over time in the ligature model (0.01 < or = p < or = 0.04). The placebo group exhibited bone loss of 1.96 +/- 0.48 and 1.40 +/- 0.56 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream showed an apparent bone gain of 0.28 +/- 0.41 and 0.78 +/- 0.47 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream containing vitamin E showed a mean bone loss of 0.41-0.48 mm per site at 3 months with improvement to an apparent bone gain of 0.31 +/- 0.44 mm per site at 6 months. The biochemical data demonstrated early and significant suppression of GCF-LTB4 by both ketoprofen formulations at 1 month, which preceded the significant suppression of GCF-PGE2 at 2 and 3 months in the ligature model (p < 0.003) and at 2 to 6 months in the spontaneous model (p < 0.02). We conclude that ketoprofen at 1% level in suitable topical vehicles can effectively inhibit GCF-LTB4 and GCF-PGE2 and positively alter alveolar bone activity in the ligature-induced model of periodontitis in the monkey.

Background Nonsteroidal antiinflammatory drugs may be particularly effective against prostaglandin-mediated, post-injury hyperalgesia and related inflammatory pain. However, their usefulness may be limited by their systemic side effects. The current study determined if local effectiveness can be achieved by low-dose intradermal nonsteroidal antiinflamatory drug administration. Methods Ten healthy volunteers were asked to make magnitude estimations of the pain induced by a contact thermal stimulator at 1 degree C increments between 43 and 51 degrees C at three 1 x 1 cm study sites on each forearm during three study phases:(1) baseline; (2) after pretreatment with 10 microl 0.9% saline (n=1 site on each forearm), 0.3 mg ketorolac (n=1 on each forearm), or nothing (n=1 on each forearm); and (3) after "injury" by a mild burn at the ketorolac- and saline-treated sites on one arm or by injection of 10 nmol bradykinin at all three sites on the other arm. The effects of pretreatment on the pain induced by thermal testing were assessed using repeated-measures analysis of variance. Results Pretreatment with ketorolac had a selective effect on the postburn injury hyperalgesia, reducing the increase in pain intensity (P

Background Visceral sensations are an important component of many clinical pain states. It is apparent that intrathecal pain relief may be more effective if appropriate combinations of drugs rather than a single agent can be used. The purpose of this study was to examine the relative contribution of opioid receptor subtypes to visceral antinociception using colorectal distension as a visceral pain model. Methods The minimum colorectal distending pressure necessary to evoke a visceromotor response (contraction of abdominal musculature) was determined before and after the administration of opioid agonists for the mu (morphine), delta ([D-Pen2, D-Pen5] enkephalin [DPDPE]), and kappa (U50,488H) opioid receptors. In addition to the three drugs administered intrathecally, U50, 488H was also administered intravenously. Results Morphine and DPDPE produced a reversible increase in threshold for activation of the visceromotor response (50% maximum possible effect [MPE] at intrathecal doses of 2.2 and 16.4 micrograms, respectively). The maximum intrathecal dose of U50,488H (100 micrograms) produced only a 20% MPE. Intravenous U50,488H produced a 50% MPE at a dose of 2.6 mg/kg. Conclusions The results suggest that spinal mu- and delta- but not kappa-opioid receptors have a significant role in the modulation of visceral nociception induced by colorectal distension. In addition, the results indicate that activation of nonspinal kappa receptors may mediate visceral antinociception.

Background Visceral pain is an important component of many clinical pain states. The perispinal administration of drug combinations rather than a single agent may reduce side effects while maximizing analgesic effectiveness. The purpose of this study was to examine the nature of interactions between an alpha 2-adrenergic agonist (clonidine) and a mu-opioid agonist (morphine), a delta-opioid agonist ([D-Pen2, D-Pen5] enkephalin [DPDPE]), or a kappa-opioid agonist (U50,488H). Methods Colorectal distension was used to elicit a nociceptive visceromotor response (contraction of abdominal musculature) in rats. The ability of intrathecally administered clonidine alone or in combination with morphine, DPDPE, or U50,488H to alter thresholds for the production of the visceromotor response was examined. Results Clonidine produced dose-dependent reduction in threshold. U50,488H, at the doses tested, showed no synergistic interaction with clonidine. Conclusions Spinal combinations of alpha 2-adrenergic and mu- or delta- but not kappa-opioid agonists may be beneficial in the control of visceral pain.

This report describes the effects of two gram-negative bacterial endotoxin (lipopolysaccharide [LPS]) preparations on hamster pregnancy outcome variables. Single intravenous challenges with Escherichia coli and Porphyromonas gingivalis LPS on day 8 of pregnancy produced dose-dependent effects on fetal weight malformation and fetal resorption with E. coli LPS having potent embryolethal effects. Premating maternal exposure to P. gingivalis produced embryolethal effects similar to those of E. coli. These data suggest that maternal exposure to P. gingivalis LPS prior to and during pregnancy can induce deleterious effects on the developing fetus.

We conducted a study to determine the sequence of cytokine and lipid mediator activation within the periodontium during the development of experimental gingivitis in humans. Crevicular fluid samples were collected from 7 previously cleaned, healthy patients at baseline, 1, 2, 3 and 4 weeks following the cessation of all oral hygiene measures. Gingival and plaque scores were taken at each visit to follow the development of gingivitis and plaque retention. Crevicular fluid samples were assayed in quadruplicate for prostaglandin E2 (PGE2), thromboxane B2 (TxB2), leukotriene B4, interleukin-1β (IL-1β) and tumour necrosis factor alpha (TNFα) by RIAs or ELISAs, maintaining site pairing to examine temporal changes. Redness scores (expressed as mean percentage of sites with redness present) increased almost linearly from a baseline value of zero to approximately 40% at 1 week, 59% at 2 weeks, 83% at 3 weeks and 100% at 4 weeks. The mean % of sites with bleeding on probing increased gradually from zero at baseline to 5% at 3 weeks and then rose abruptly to 25% at 4 weeks. CF-PGE2 and CF-TxB2 levels remained fairly stable at baseline levels for the first 3 weeks then rose sharply by 2.5- and 2-fold, respectively, at 4 weeks. CF-LTB4 levels increased 2-fold by 1 week and 4-fold by 4 weeks. The CF levels of IL-1β increased abruptly from mean baseline values of 16.5±9.3 ng/ml to 131±76.0 ng/ml at 1 week and remained at this level for the duration of the experiment. CF-TNFα levels were non-detectable throughout the experiment (i.e. < 2 ng/ml). These data suggest that LTB4 and IL-1β are involved in the earliest stages of gingivitis and that increases in the cyclooxygenase products PGE2 and TxB2 occur later and are associated with an increase in bleeding scores.

Ligature-induced periodontitis was monitored for 6 months in eight Macaca mulatta monkeys to examine clinical status, radiographic bone level, and crevicular fluid (CF) levels of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and leukotriene B4 (LTB4). A split-mouth design was used, with eight ligated teeth and eight contralateral nonligated teeth which develop soft-chow-promoted (spontaneous) disease. Ligated sites experienced an average attachment loss of 0.94 mm per site and linear bone loss of 0.88 mm per site, with spontaneous-periodontitis sites experiencing approximately half the loss of ligated sites. The CF mediator levels showed increased levels of PGE2 and TxB2 at the ligated sites, as compared with the spontaneous sites, with no significant contralateral differences in the IL-1 beta or LTB4 responses. The concentrations of LTB4 in CF reached an early threefold peak over the baseline level at 1 month. By 2 months there was a statistically significant threefold elevation in CF-PGE2 in the ligated sites and a twofold elevation in the spontaneous sites as compared to the baseline level (P = 0.041 and 0.008, respectively). The monocyte product IL-1 beta increased sharply at 2 months and returned to the baseline level by 6 months at both ligated and nonligated sites. Tumor necrosis factor alpha in CF was below the limit of detection at all sites throughout the experiment (i.e., < 2 ng/ml). The selective elevation of both PGE2 and TxB2 in ligated sites, compared with levels in spontaneous sites, in the presence of similar levels of LTB4 and IL-1 beta provides further evidence that these molecules regulate the magnitude of the tissue-destructive response in progressive periodontitis.

This study examined the feasibility of using colorectal distention as a noxious visceral stimulus in rat pregnancy-induced analgesia studies as well as the influence of naloxone on the pregnancy-induced changes in the behavioral response to a noxious visceral stimulus. In the first part of the study, we compared the effects of pregnancy on several forms of noxious stimulation (colorectal distention, hypertonic saline induced writhing, tail flick, and hot plate). After determination of prepregnant baseline values, one group of rats (n = 35) was mated and retested on days 7 and 21 of gestation and 1, 3, 5, 7, and 14 days after parturition. After baseline determinations on day 21 and postpartum day 1, the animals received a subcutaneous injection of naloxone 1.0 mg/kg and were retested. A nonpregnant control group of animals (n = 7) was tested in the same manner. On day 21 of gestation and postpartum days 1 and 3, significant changes (higher threshold or longer latency to response) were observed after all but the writhing test. High-dose naloxone (1.0 mg/kg) significantly reduced the increases observed on day 21 and post-partum day 1. Nonpregnant rats demonstrated no significant change on any test day. The second part of the study evaluated a possible influence of low-dose naloxone on pregnancy-induced analgesia to visceral stimulation (colorectal distention) in another group of pregnant rats (n = 44). The significant increase in threshold on day 21 of gestation was not changed by intravenous (i.v.) naloxone 1.0, 2.3, or 3.0 micrograms/kg, whereas 5.0 and 20.0 micrograms/kg naloxone significantly decreased the observed pregnancy-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of enflurane on the firing activity (spikes/sec) of the inspiratory neurons of the dorsal respiratory group (DRG) of the medulla oblongata was studied in decerebrate, paralyzed, mechanically ventilated cats before and after bilateral cervical vagotomy. Inspiratory neuronal activity, phrenic neurogram, arterial blood pressure, tracheal pressure, and end tidal CO2 concentration were recorded. Cells whose firing activity was in phase with that of the phrenic nerve were considered inspiratory neurons. Administration of 1 and 2% enflurane in oxygen produced gradual, significant, and dose-dependent depression of the cell activity with cervical vagi either intact or severed. Recovery of the cell activity occurred after termination of enflurane administration. In cats with intact vagi, 10 min after introduction of 1 and 2% enflurane, the cell activity (mean +/- SE) expressed as percentage of the control was 70 +/- 6% (P less than 0.05) and 48 +/- 5% (P less than 0.01), respectively. Bilateral cervical vagotomy did not affect the degree of cell depression due to enflurane. Hypercarbia induced by inhalation of 5% CO2 increased cell activity, but it did not block enflurane-induced cell depression, although it reduced it. It may be concluded that enflurane depresses the activity of the inspiratory neurons of the DRG. The results also suggest that the respiratory depressant effect of enflurane has a central component and that the DRG region may serve as a site to mediate the enflurane-induced respiratory depression.

Measurements of the heat capacity, Cp, from 0.6 to 15 K can be represented by Cp=(0.32+or-0.02)T3 mJ mol-1 K-s ( theta D0=265+or-10 K) below 10 K. Linear thermal expansivities parallel ( alpha /sub ///) and perpendicular ( alpha perpendicular to ) to the symmetry axis from 2 to 120 K show marked anisotropy; alpha perpendicular to is negative below 10 K (while alpha /sub /// remains positive) but becomes positive and much larger than alpha /sub /// above 50 K. The Gruneisen parameter, gamma , increases from approximately=1 at 3 K to +1.4 at 30 K and is approximately=0.9 room temperature.

Extracellular activity was recorded from single spinal dorsal horn neurons in physiologically intact, awake, drug-free cats before and after the intravenous administration of 20 mg/kg pentobarbital (Pb). Pb produced a series of changes in response properties that reflect a significant moment-to-moment plasticity of some spinal dorsal horn neurons. Pb administration unmasked the ability of some low-threshold (LT) neurons to respond to noxious mechanical or thermal stimuli resulting in their being reclassified as wide dynamic range (WDR) neurons. Pb also appeared to unmask an afterdischarge in some neurons following noxious mechanical stimulation. In addition, some neurons appeared to be better able to signal changes in the intensity of mechanical stimulation after Pb. Neuronal receptive fields for low threshold stimulation were reduced in many instances but enlargement was also observed. The responses of some neurons to peripheral stimulation were unchanged by Pb. We hypothesize that the relatively low doses of Pb used in the study reduced tonic inhibition of some spinal dorsal neurons although the observed effects could have been produced by excitation.

The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. In a note attached to that definition (http://www.iasppain.org.terms-p.html#Pain), the IASP further states that “unpleasant, abnormal experiences (dysesthesias) may also be pain but are not necessarily so because, subjectively, they may not have the usual sensory qualities of pain.” While everyone would agree that itch does not have the sensory qualities of pain, for those patients with intense, unrelenting itch the sensory and emotional experiences can be as unpleasant as pain. Clinical colleagues have told me anecdotal stories of patients with itch due to spinal intrathecal opioid administration who indicated a desire to stop the opioid administration because they would rather experience the pain than the itch. It is difficult to define the number of patients whose quality of life is adversely impacted by uncontrolled itch. However, as suggested in Table 1 by a partial list of dermatologic and systemic diseases that are associated with itch, it is likely that the number is quite high. Because itch does cause unpleasant sensory and emotional experiences in a large number of humans, it seems appropriate to focus more attention on efforts to understand the physiology of itch. In addition, because most current treatments for itch are quite inadequate, it also seems appropriate to attempt to develop better treatment modalities for patients suffering with intense, unrelenting itch. This topic is also of potential interest

UNLABELLED Inhaled anesthetics depress the response of spinal dorsal horn low-threshold (LT) neurons to peripheral receptive field stimulation. Part of that depression may be mediated by anesthetic interactions with gamma-aminobutyric acid type A (GABA(A)) and strychnine-sensitive glycine inhibitory neurotransmitter systems. In this electrophysiological study, we attempted to antagonize halothane depression of LT neurons by administering bicuculline (a competitive GABA(A) antagonist) and/or strychnine (a competitive glycine antagonist) systemically, alone or in combination, to decerebrate, spinal cord-transected rats. We observed that both bicuculline and strychnine, alone or in combination, significantly but only partially reversed halothane depression of LT neuronal responses to receptive field stimulation. The inability of bicuculline and strychnine, alone or in combination, to completely reverse halothane depression suggests that although GABA(A) and glycine systems are involved in the observed halothane depression, additional mechanisms of action are also required for halothane depression of LT spinal sensory neurons. IMPLICATIONS The results of this study support the hypothesis that halothane depression of spinal sensory neurons is mediated, but not completely, by the anesthetic effects on gamma-aminobutyric acid type A and strychnine-sensitive glycine neurotransmitter systems.

This review article focuses on the suppression of sensory transmission by inhalational anesthetics at the spinal cord level. Volatile anesthetics (e.g. halothane and isoflurane) suppress neuronal responses evoked by both noxious and non-noxious stimuli. This suppression is mediated largely by activation of GABAA and glycine receptors systems in the spinal dorsal horn. Depression of spinal glutamate receptor systems is also probably involved. The analgesic action of nitrous oxide is produced by activation of supra-spinal descending inhibitory systems, not by direct action on the spinal cord. Activation of the descending inhibitory systems by nitrous oxide causes release of noradrenaline in the spinal dorsal horn, and activates alpha 2 adrenergic receptor systems, resulting in depression of neuronal responses evoked by noxious stimuli. GABAA and glycine receptor systems in the spinal dorsal horn are also important components of nitrous oxide anesthesia in depressing neuronal responses evoked by non-noxious stimuli. Although excitation or inhibition of GABAA, glycine, alpha 2 adrenergic and glutamate receptors systems is an important action of inhalational anesthetics, influence of inhalational anesthetics on interactions among these receptor systems has yet to be studied.

UNLABELLED We recently reported that gamma-aminobutyric acid type A- and strychnine-sensitive glycine receptor systems partially mediate halothane depression of spinal dorsal horn low-threshold neurons. Serotonin subtype 3 (5-HT(3)) receptors belong to the same ligand-activated ion-channel family as gamma-aminobutyric acid type A- and strychnine-sensitive glycine receptors, so we examined the possible involvement of 5-HT receptor systems in halothane depression of spinal sensory neurons. Extracellular recordings of spinal low-threshold neurons were obtained in decerebrate, spinally transected rats. Receptive field size and brush-induced activity were recorded in the presence or absence of 5-HT antagonists and in the presence or absence of 1.1% (1 minimum alveolar anesthetic concentration) halothane. In the absence of halothane, antagonists had no effect on receptive field size or brush-induced activity. In the presence of halothane, methysergide, a nonselective 5-HT antagonist, and tropisetron, a selective 5-HT(3) antagonist, significantly reversed the halothane-induced reduction in receptive field size but did not alter halothane depression of brush-induced activity. Methiothepin, a 5-HT(1) antagonist, and ketanserin, a 5-HT(2) antagonist, did not reverse halothane depression. These results support the hypothesis that 5-HT(3) receptors partially mediate some inhibitory effects of halothane on spinal dorsal horn neurons. IMPLICATIONS The results of this study support the hypothesis that halothane depression of spinal sensory neuronal responses to low-intensity stimuli is mediated, to a minor extent, by serotonin subtype 3 neurotransmitter systems.

We report here an efficient means of epidural catheter placement through atlanto-occipital membrane in rats.Male SD rats (n = 84) were divided into lumbar (n = 48) and cervical (n = 36) groups. Under sterile technique, PVC V-1 tubing was inserted and advanced caudally targeted to the C 4 or L 4 level. Analgesic efficacy and duration were measured by injecting increments of 2% lidocaine until a maximum paw withdrawal latency time from a radiant heat thermal stimulator. Rats (n = 6 each day) were sacrificed and an autopsy was performed to observe both the laterality of the catheter tip and the proliferation of fibrous tissue around the catheter.The volume of lidocaine and its duration was 52 +/- 17 microliters and 27 +/- 13 min (mean +/- SD) in lumbar, 30 +/- 10 microliters and 26 +/- 9 min in cervical group. In lumbar group, two catheters penetrated the dura. The remaining catheters were confirmed to be in the epidural space within L 4 +/- 1 or C 4 +/- 2 segment. Lumbar catheter tips were almost equally distributed between the center, left and right, while cervical catheter tips were distributed between left and center portion of the epidural space. The severity of tissue proliferation was time dependent. The proliferation of fibrotic tissue seemed more rapid in cervical than lumbar group.Although this approach for epidural catheter placement is efficient and produces excellent drug effects on day 3 after implantation, as reported by others, rapid development of fibrous tissue around the catheter quickly limits the usefulness of the epidural catheter.

The two platinum complexes [[Pt(dien)]2mu-dpzm]4+ and trans-[Pt(NH3)2(mu-dpzm)2]2+(dpzm = 4,4'-dipyrazolylmethane) have been synthesized and their DNA binding and cytotoxicity studied in order to evaluate the potential of square-planar platinum complexes as DNA groove binding anti-cancer agents. 1H-NMR spectroscopy was used to study the binding of both metal complexes to the dodecanucleotide d(CGCGAATTCGCG)2. For both platinum complexes, a considerable number of intermolecular NOE contacts were observed in NOESY spectra of the platinum complex bound dodecanucleotide. The NOE data demonstrated that each platinum complex bound in the minor groove at the central AATT region. Neither platinum complex appeared to induce any major DNA conformation change. In vitro cytotoxicity studies in the murine leukaemia cell lines L1210 and L1210/cisR showed that trans-[Pt(NH3)2(mu-dpzm)2]2+ had some activity (IC50: 64 and 32 microM respectively) while the [[Pt(dien)]2mu-dpzm]4+ complex showed no activity at all (200 microM). The results indicate that it may be possible to synthesize platinum complexes that are useful as groove binding agents in the treatment of cancer.

The lattice vibrational spectra, g( nu ), of YBa2Cu3O7 and Bi2Sr2CaCu2O8+x, are used to predict qualitatively the observed behaviour of their lattice specific heat. The temperature dependence of the Debye temperature, theta D(T), is calculated from published g( nu ) spectra for both YBa2Cu3O7 and Bi2Sr2CaCu2O8+x, and compared with the experimentally derived values of theta D(T). For both ceramics there is poor quantitative agreement between the calculation and experiment, which the authors attribute to difficulties in accurately determining g( nu ) at low frequencies.

Ota, Kouichi, Tadao Yanagidani, Kazuhiro Kishikawa, Yuji Yamamori, and J. G. Collins. Cutaneous responsiveness of lumbar spinal dorsal horn neurons is reduced by general anesthesia, an effect dependent in part on GABAA mechanisms. J. Neurophysiol. 80: 1383–1390, 1998. Extracellular activity was recorded from single spinal dorsal horn neurons in both chronic cat and acute rat models. This was done to define the effects of anesthesia on the processing of sensory information elicited by nonnoxious tactile stimulation of peripheral receptive fields (RFs). In the chronic cat model, baseline data were obtained in physiologically intact, awake, drug-free animals before anesthetic administration (halothane 1.0–2.0%). This made it possible to compare and contrast activity of each cell in the drug-free and anesthetized state. Halothane effects were confirmed in the acute rat model (anesthetized, spinally transected, and in some cases decerebrate). In addition, the γ-aminobutyic acid-A (GABAA)-receptor antagonist picrotoxin (2 mg/kg) was administered intravenously to verify that the observed halothane effect on spinal dorsal horn neurons was mediated by an interaction with GABAA-receptor systems. Halothane effects on three separate measures of response to nonnoxious tactile stimuli were observed in the chronic cat model. Halothane produced a significant, dose-dependent reduction in the low-threshold RF area of the neurons studied. Halothane also caused a significant reduction in neuronal response to RF brushing (dynamic stimulus) and to maintained contact with the RF (static stimulus). A dose dependency was not observed with these latter two effects. Neurons with a predominant rapidly adapting response seemed to be less susceptible to halothane suppression than slowly adapting cells. In the acute rat model an increase in halothane caused a reduction in neuronal response similar to that seen in the cat. The intravenous administration of 2 mg/kg of picrotoxin by itself caused no significant change in RF size or response to brushing. However, the same amount of picrotoxin did cause a 50% reversal of the halothane-induced reduction in RF size without causing a significant change in the halothane effect on response to RF brushing. In contrast to work recently reported in a chronic sheep model, halothane causes a significant reduction in spinal dorsal horn neuronal response to tactile stimulation of peripheral RFs. This effect is caused by, in part, but not exclusively, to GABAA-neurotransmitter systems. However, the relative influence of GABAA systems may vary with the nature of the stimulus.

This report presents an update of the prevalence of selected chronic conditions in the United States. Its purpose is to provide prevalence data by age, sex and age, race and age, family income, and geographic region for major chronic condition systems. It further assesses the percent of selected conditions that cause activity limitation, the percent for which a physician was consulted, and the percent that caused hospitalization. Conditions with the highest prevalence and those causing the most disability days are also analyzed. Trends in prevalence rates for the conditions with highest prevalence are examined as well. Information for this report is based on data collected during the National Health Interview Survey (NHIS) for the years 1990, 1991, and 1992. This is a continuing nationwide survey of households for which a probability sample of the civilian noninstitutionalized population of the United States is interviewed by the U.S. Bureau of the Census regarding the health and other characteristics of each member of the household. The sample for the years 1990-92 was composed of 142,638 households containing 368,075 persons. Each household was administered one of six of the chronic conditions system lists. Deformities or orthopedic impairments was the most frequent chronic condition reported with almost 35 million conditions. Other conditions high in prevalence were chronic sinusitis, arthritis, and high blood pressure with annual averages of 33.7, 31.8, and 27.6 million conditions, respectively. Mental retardation and multiple sclerosis caused the highest percents of activity limitation among persons afflicted, 87.5 percent and 69.4 percent, respectively. Deformities and other orthopedic impairments, arthritis, and heart disease caused the highest numbers of restricted activity days and bed disability days per year, whereas, malignant neoplasms of the lung, bronchus, and other respiratory sites, caused the highest number of restricted activity days per year, per condition reported, 96.1 days. In little more than a decade, the prevalence rate from asthma has increased almost 50 percent and the rate from chronic bronchitis has increased 46 percent.

The goal of this study was to provide new data regarding levels of inflammatory and growth factor mediators and bacterial pathogens associated with failing implants, as compared to healthy implants. Twenty-one patients with failing implant sites (group 1) and 8 patients with only healthy implants (group 2) were included. Fifteen of the 21 failing implant patients (group 1) also presented with at least one stable nondiseased implant. Plaque samples were examined, using DNA oligonucleotide probes for 40 different microbes. Gingival crevicular fluid samples were collected for the analyses of catabolic bone resorbing agonists prostaglandin E2 (PGE2), interleukin-1 beta (IL-1 beta) and IL-6 and anabolic bone-forming growth factors transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF). Although positive trends were noted, there were no significant differences in any of the microbial, inflammatory, or growth factors mediators comparing failing to stable implants in group 1. This study found greater detection frequencies of P. nigrescens, P. micros, F. nucleatum ss vincentii, and F. nucleatum ss nucleatum, as well as significant elevations in GCF levels of PGE2, IL-1 beta, and PDGF in mouths with failing implant sites as compared to mouths with healthy control implants. Risk appears to be primarily at a patient level and secondarily at a site or implant level from a clinical, microbial (P. micros and P. nigrescens), and biochemical (PGE2 and IL-1 beta) perspective. Furthermore, the counts of P. nigrescens and P. micros were found to correlate with concentrations of PGE2 at a site level.

National estimates of average annual health indexes for the civilian noninstitutionalized population of the United States are presented in this report according to selected socioeconomic characteristics of the family. These estimates are based on data from the National Health Interview Survey (NHIS) in 1988, 1989, and 1990. Health indexes presented include percent limited in activity; percent with fair or poor respondent-assessed health status, restricted activity days, bed disability days, work-loss days, and school-loss days; percent with a physician contact in past year; numbers of annual physician contacts per person per year; percent with a hospital episode in the past year; days per short-term hospital stay; and incidence of acute conditions. This report includes the findings that persons living by themselves reported a higher percent of limitations in activity, high rates of disability days, more physician contacts per year, and a higher incidence rate from acute conditions than all persons 45-64 years of age. Persons in all four age groups reported higher percents with limitations of activity and higher percents with fair or poor health status in families in which the educational level of the responsible family adult member was less the 12 years than in families where the responsible adult was better educated. Both males and females, and white persons and black persons, in each of the age groups 18 years and over who were living with a spouse reported lower percents of limitations in activity than did persons living in other family relationships.

This report includes a review of previous research on the reporting of ambulatory medical visits in household surveys, describes the methods used in the Health Interview Evaluation Survey, and presents results relating to the reporting of 2-week doctor visits.

The binding of Co(NH3)6(3+), delta-Co(en)3(3+) and delta-Rh(en)3(3+) to the dodecanucleotide d(CAATCCGGATTG)2 has been studied by 1H NMR. Addition of Co(NH3)6(3+), delta-Co(en)3(3+) or delta-Rh(en)3(3+) to d(CAATCCGGATTG)2 induce a similar pattern of chemical shift movements of the dodecanucleotide base protons. Analysis of the chemical shift changes as a function of added metal-ion complex shows that the binding affinity for d(CAATCCGGATTG)2 decreases in the order: delta-Co(en)3(3+)delta-Rh(en)3(3+)Co(NH3)6(3+). Addition of a saturating ratio of delta-Co(en)3(3+) to d(CAATCCGGATTG)2 induces a selective B to A type-DNA transition for the central CpG segment of the dodecanucleotide, with all other nucleotide residues maintaining the B-type conformation.

Recent evidence strongly supports the importance of spinal sites of action for the ability of general anesthetic agents to block response to noxious stimuli. This study was designed to examine possible spinal anesthetic effects on non-noxiously evoked activity. Three groups of rats were prepared for acute experiments in which the response of spinal dorsal horn neurons to low threshold receptive field (RF) stimulation was evaluated. In each animal in each group extracellular activity was recorded from a single spinal dorsal horn neuron. A low-threshold RF of each neuron and, at times, the sensitivity to low-threshold stimulation of multiple sites in the RF were determined under baseline conditions (light anesthesia or decerebrate). In Group 1, reversible cooling of the thoracic spinal cord in the presence of either 0.5% or 1% halothane anesthesia caused no change in RF size. However, an increase from 0.5% to 1% halothane caused a 53% decrease in RF size both in the presence and absence of a reversible cold block of the spinal cord. In Group 2, animals with spinal cords transected at the thoracic level had a similar change in low-threshold receptive field size (52%) when halothane concentrations were increased from 0.5% to 1%. Testing sensitivity within the RF areas indicated that the silenced areas at the fringe of the receptive field could still elicit activation of spinal dorsal horn neurons but at a higher threshold. In the final group of animals, decerebration and spinal cord transection allowed us to compare effects of 0.5% and 1% halothane with an anesthetic free baseline. Here, again, a dose-dependent reduction in RF area was observed although the baseline RFs were significantly smaller than those in Groups 1 and 2. These results demonstrate that the reduction in low-threshold receptive field size due to the administration of the inhalation anesthetic halothane occurs in the absence of descending modulation from supraspinal sites. This implicates the spinal dorsal horn as a potentially important site of action for general anesthetics. These results also support the spinal cord as an important tool to study the pharmacology responsible for anesthetic effects on sensory processing.

The existence of prostaglandin (PG) receptors in the spinal cord has been demonstrated, but their role in sensory processing is not yet well defined. PGE1 is widely used clinically as a vasodilator. The present study was designed to investigate the effects of intrathecally administered PGE1 on the transmission of different types of sensory information, including that associated with noxious somatic, noxious visceral, and non-noxious somatic stimulation. The tail-flick (TF) test was employed to measure responses to noxious somatic stimuli, and the colorectal distension test was used to examine responses to noxious visceral stimuli. Withdrawal response to mechanical pressure produced by Semmes-Weinstein mono-filaments (SWMs) was measured as an assessment of sensitivity to non-noxious mechanical somatic stimulation. TF latencies and colorectal distension thresholds decreased for a short time (10–20 min) following the intrathecal (i.t.) administration of both 100 ng or 500 ng of PGE1. In sharp contrast to these short duration effects, there was a long-lasting increase in agitation scores (allodynia) produced by 3 different intensities of SWMs (0.217, 0.745 and 2.35 g) after administration of PGE1. The changes in agitation scores to SWMs were dependent on the dose of PGE1 and the intensity of stimulation. This increase of agitation score was seen when PGE1 was administered through the i.t. catheter or by direct i.t. puncture and the increase lasted for at least 2 days after drug administration. Intrathecal administration of saline, however, did not produce any changes in TF latencies, colorectal distension thresholds, or agitation scores produced by SWMs. No significant histological difference was seen between spinal cords exposed to 500 ng PGE1 and saline 48 h after drug administration. These results demonstrate that PGE1 may trigger a hypersensitive (allodynic and/or hyperalgesic) state in sensory processing pathways at the spinal level. They also indicate that long-lasting changes in processing of non-noxious, but not noxious, information produced by PGE1 continues after the disappearance of the direct action of PGE1.

Background Pentobarbital reduces low-threshold receptive field (RF) size and enhances responses of some spinal dorsal horn neurons to noxious stimulation in cats. To better understand the effects of general anesthetics on spinal sensory processing, this study was designed to determine if intravenous propofol and ketamine have similar effects. Methods Spinal dorsal horn neuronal responses to RF stimulation were observed in physiologically intact, awake, drug-free cats. After baseline observations were made, the effects of propofol (7.5 or 10 mg/kg intravenous) or ketamine (10 mg/kg intravenous) on those neuronal responses were observed. Results Propofol is capable of producing a profound reduction in low-threshold RF size. Propofol also depressed neuronal responses to non-noxious and noxious RF stimulation in many of the neurons tested. Ketamine was not observed to produce any change in either RF size or neuronal response to non-noxious RF stimulation. Conclusions General anesthetics that interact with gamma aminobutyric acid receptors may significantly depress low-threshold sensory information within the spinal dorsal horn. This may contribute to anesthetic-induced loss of sensation. Lack of a ketamine effect suggests an absence of n-methyl-d-aspartate receptor involvement in spinal dorsal horn processing of low threshold sensory information.

The present study examined interactions between mu and delta opiate subtypes and serotonin. Noxious activity evoked by radiant heat (51 degrees C, 8 sec) was extracellularly recorded from single discriminated wide dynamic range (WDR) neurons in decerebrate spinally transected cats. DAGO (mu selective opioid agonist) 1 microgram or DPDPE (delta selective opioid agonist) 30 micrograms was combined with serotonin (n = 6 each) 250 micrograms. The dose of each drug by itself when administered intrathecally produced no suppression of noxiously evoked activity. Although the combination of DAGO and serotonin produced no significant suppression of noxiously evoked activity, DPDPE and serotonin produced significant suppression to 72.8 +/- 8.0 % (mean +/- SEM) of control values (P0.01). Intravenously administered naloxone 0.1 mg reversed the suppression produced by the DPDPE-serotonin combination. Our results suggest that combinations of serotonin and delta selective opiates may be more effective in suppressing noxiously evoked activity than combinations with mu selective opiates.

BACKGROUND Clinically, epidural coadministration of opioids and local anesthetics has provided excellent analgesia for various types of pain. However, information about the interaction of these drugs when administered epidurally is limited. Therefore, we evaluated the antinociceptive interaction between morphine and lidocaine on both somatic and visceral noxious stimuli in the rat. METHODS Male Sprague-Dawley rats weighing 300-350 g had epidural catheters implanted at T13-L1. Every rat was tested with both the tail flick test, a somatic noxious stimulus, and the colorectal distension test, a visceral noxious stimulus. In the colorectal distension test, the response threshold was defined by the pressure within the intracolonic balloon required to trigger abdominal contraction. Tail flick latency and colorectal distension threshold were measured before and for 180 min after the administration of morphine, lidocaine, or combinations of those drugs. To characterize the interaction, isobolographic analysis was performed with a fixed morphine: lidocaine dose ratio of 1:1,000. RESULTS Epidural morphine (0.1-10 micrograms) and lidocaine (100-800 micrograms) increased the tail flick latency and colorectal distension threshold in a dose- and time-dependent fashion. The epidural injection of morphine (0.1-1 microgram) mixed with lidocaine (100 or 200 micrograms) significantly increased the peak effect and prolonged the duration of effects compared with each drug alone in both nociceptive tests. Areas under the curves, calculated to express overall magnitude and duration of antinociceptive effects, were significantly increased by combinations as compared with each drug alone, especially with morphine 0.1 microgram and lidocaine 100 or 200 micrograms, each of which alone produced no change in the area under the curve. Isobolographic analysis revealed that epidural morphine and lidocaine interact synergistically at 10, 20, and 30 min after injection in both somatic and visceral nociception tests. Both potency ratio analysis and fractional analysis confirmed the finding of the isobolographic analysis. Epidural naloxone antagonized the antinociceptive effects produced by the combination. CONCLUSION These data demonstrate that epidurally coadministered morphine and lidocaine produce synergistic analgesia and prolong the duration of analgesia in tests of somatic and of visceral nociception.

A clinical trial was undertaken to examine the effects of a potent cyclooxygenase inhibitor, flurbiprofen, on both developing and established gingivitis in humans. 21 subjects with healthy gingiva abstained from all oral hygiene procedures for 21 days. 7 subjects were prescribed flurbiprofen, 50 mg b.d. beginning from baseline and a control group (Cl, n = 14) were given placebo. Gingival redness and bleeding on probing were assessed at baseline, 7, 14 and 21 days. Crevicular fluid (GCF) samples were also taken to determine concentrations of PGE2, TxB2 and LTB4 at baseline and at 21 days. Results show that flurbiprofen significantly inhibited the development of redness and bleeding (p < 0.001) effects which were associated with a significant inhibition of TxB2 (p < 0.05). There were no apparent flurbiprofen effects on GCF-PGE2 or GCF-LTB4 during this 21-day gingivitis, model To assess the effects of flurbiprofen on established experimental gingivitis, the model was extended to 28 days. On day 21, the Cl group was subdivided into 2 groups of 7 subjects. One group was prescribed flurbiprofen (50 mg b.d.) for 7 days and controls (C2) continued to take placebo. All subjects continued to abstain from tooth cleaning. Pretreatment (day 21) and post-treatment (day 28) comparisons showed that flurbiprofen again significantly inhibited bleeding (p < 0.001), but did not affect redness. Control subjects demonstrated a significant elevation in gingival bleeding on day 28, and this was associated with significant rises in GCF-PGE2 (p < 0.001), GCF-TxB2 (p < 0.01) and GCF-LTB4 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The pathogenesis of periodontal tissue destruction involves the orchestrated sequential activation of several components of the host response, each of which have the potential for providing diagnostic information regarding the health or disease status of the periodontium. These events include the bacterial triggering of serum components, the release of vasoactive compounds, the recruitment of inflammatory cells, the activation of phagocytes, the local secretion of immunoglobulins and inflammatory mediators, as well as connective tissue remodeling. For purposes of diagnosis, much attention has been directed toward the measurement of local levels of specific byproducts of the pathogenic process either within the tissues or in the adjacent crevicular fluid. These are site-directed assessments of the local concentration of these byproducts, and with the important exception of antibody levels, very few byproducts of the periodontal pathogenic process have been studied on a systemic level. However, since the risk associated with periodontal disease progression is primarily patient-based and secondarily site-based, there is an increasing need to identify patients at risk for intervention strategies. Furthermore, there are substantial data that periodontal diseases are specific infections that occur in an appropriately susceptible host. The expression of periodontal disease has a strong genetic component, which presumably defines the host's response thereby affecting susceptibility. For this reason, there is increased interest in defining those elements of the host response which result in susceptibility to disease. The ultimate objective of a diagnostic strategy is to identify patients who are potentially at risk for acquiring disease to enable preventive measures.

This report describes the clinical and microbiological features of 30 refractory patients and their response to a combined local and systemic therapy at 6 weeks and 3 years following treatment. The refractory treatment protocol (RefTx) consisted of a 2-week regimen of amoxicillin/clavulanate potassium in conjunction with professional, intrasulcular delivery of povidone iodine, and chlorhexide mouthwash rinses b.i.d. Eighty-seven percent of the patients had favorable clinical responses to the RefTx and could be divided into 3 groups (A, B, C) based upon initial flora patterns and the shifts that occurred following treatment. Pretreatment prevalence of Porphyromonas gingivalis (P.g.) was 36.7%. The RefTx was effective in reducing P.g. below detection levels in 10 of the 11 positive patients at P0.01; each of these 10 patients (Group A) demonstrated significant gain in attachment. Other black-pigmented Bacteroides species (OBP) were isolated from 70% of the patients at baseline. Nine of these patients did not harbor P.g., showed clinical improvement upon treatment, and were OBP negative following treatment (Group B). Group C patients (7) demonstrated clinical improvement with therapy and did not fit into either Group A or B based upon microbial patterns. Group D patients (4) did not show clinical improvement with 3 patients harboring either P.g. or OBP after treatment. The RefTx was effective at reducing probing pocket depth with a 56% decrease in the number of pockets greater than 6 mm at 6 weeks. This was accompanied by an overall gain ofor = 1 mm of probable attachment in 45% of all sites. The clinical effects of the RefTx were shown to persist at 34.3 months with an apparent attachment gain ofor = 1 mm in 41.2% of sites. These data suggest that P.g. and OBP are important pathogens in refractory periodontitis and that the RefTx protocol is an acceptable, non-invasive alternative for the management of these patients.

The clinical success of perispinal administration of opiates for pain relief has demonstrated the power of manipulating the neurochemistry of the spinal cord. This article briefly discussed reasons for increased interest in new spinal agents and some of the issues associated with determining their clinical safety.