Orofacial mechanoreceptors in humans: encoding characteristics and responses during natural orofacial behaviors

We used microneurography to characterize stimulus-encoding properties of low-threshold mechanoreceptive afferents in human orofacial tissues. Signals were recorded from single afferents in the infraorbital, lingual and inferior alveolar nerves while localized, controlled, mechanical stimuli were delivered to the facial skin, lips, oral mucosa and teeth. We likewise analyzed activity in these afferents during orofacial behaviors such as speech, chewing and biting. The afferents in the soft tissues functionally resemble four types described in the human hand: hair follicle afferents, slowly adapting (SA) type I and type II afferents and fast adapting (FA) type I afferents. Afferents in the facial skin, lips and buccal mucosa respond not only to contact with environmental objects, but also to contact between the lips, changes in air pressure generated for speech sounds, and to facial skin and mucosa deformations that accompany lip and jaw movements associated with chewing and swallowing. Hence, in addition to exteroceptive information, these afferents provide proprioceptive information. In contrast, afferents terminating superficially in the tongue do not signal proprioceptive information about tongue movements in this manner. They only respond when the receptive field is brought into contact with other intraoral structures or objects, e.g. the teeth or food. All human periodontal afferents adapt slowly to maintained tooth loads. Populations of periodontal afferents encode information about both which teeth are loaded and the direction of forces applied to individual teeth. Most afferents exhibit a markedly curved relationship between discharge rate and force amplitude, featuring the highest sensitivity to changes in tooth load at low forces (below 1 N). Accordingly, periodontal afferents efficiently encode tooth load when subjects first contact, hold, and gently manipulate food by the teeth. In contrast, only a minority of the afferents encodes the rapid and strong force increase generated when biting through food. We conclude, that humans use periodontal afferent signals to control jaw actions associated with intraoral manipulation of food rather than exertion of jaw power actions.     

Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study

Summary Patients with combat-related posttraumatic stress disorder (PTSD) show altered cognitive and affective processing and symptomatic responding following exposure to trauma reminders. Previous symptom provocation studies using brain imaging have involved Vietnam veterans. In this study neural correlates were investigated in patients with PTSD resulting from trauma in more recent war zones. ¹⁵Oxygen water and positron emission tomography were used to measure regional cerebral blood flow (rCBF) in patients with war- and combat-related chronic PTSD during exposure to combat and neutral sounds. Self-reports and heart rate confirmed symptomatic responding during traumatic stimulation. The war-related condition, as compared to the neutral, increased rCBF in the right sensorimotor areas (Brodmann areas 4/6), extending into the primary sensory cortex (areas 1/2/3), and the cerebellar vermis. RCBF also increased in the right amygdala and in the periaqueductal gray matter adjacent to the pons. During provocation rCBF was lowered in the right retrosplenial cortex (areas 26/29/30 extending into area 23). Symptom provocation in PTSD promote sensorimotor, amygdaloid and midbrain activation. We conclude that perceptually induced symptom activation in PTSD is associated with an emotionally determined motor preparation and propose that subcortically initiated rather than cortically controlled memory mechanisms determine this pattern. Received: 14 November 2001 / Accepted: 1 March 2002     

Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea

OBJECTIVES: Our objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT-11) and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) and to investigate the pharmacokinetic-pharmacodynamic relationships between drug exposure and diarrhea, the major dose-limiting toxicity. METHODS: Data were obtained from 109 patients (65 men and 44 women) who received 1.5-hour (range, 0.75- to 2.25-hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m(2); 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration-time profiles. The area under the concentration-time curve from time zero to 60 hours [AUC (0-60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model. RESULTS: A 3-compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN-38 and SN-38G showed 2-compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady-state (V(SS)) was 263 L. The clearance divided by formation fraction (F(m)) was 712 L/h and 66.8 L/h for SN-38 and SN-38G, respectively. The V(SS)/F(m) was 72,000 L for SN-38 and 85.4 L for SN-38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0-60) and diarrhea scores were found for irinotecan (P <.05) and SN-38G (P <.01) but not for SN-38 or the biliary index. CONCLUSIONS: In this population analysis, irinotecan and SN-38G AUC values were appropriate predictors of the risk for diarrhea, and SN-38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent.     

Work load and work hours in relation to disturbed sleep and fatigue in a large representative sample

OBJECTIVE: To study the relation between work and background factors on the one hand and disturbed sleep and fatigue on the other. METHOD: A representative national sample of 58,115 individuals was selected at regular intervals over a period of 20 years and interviewed on issues related to work and health. The data were subjected to a multiple logistic regression analysis. RESULTS: The number of cases was 18,828 (32.8%) for fatigue and 7347 (12.8%) for disturbed sleep. For disturbed sleep, the significant predictors became: female gender, age above 49 years, present illness, hectic work, physically strenuous work, and shift work. For fatigue, the significant predictors became female gender, age below 49 years, high socioeconomic status, present illness, hectic work, overtime work, and physically strenuous work. CONCLUSION: Work stress, shift work, and physical workload interfere with sleep and are related to fatigue.     

Shame reactions after suicide attempt

Shame reactions were spontaneously described by 13 of 18 patients interviewed in a qualitative study investigating experiences of care following a suicide attempt. The shame data from the interview study were extracted, analysed separately, and are reported in this article. The shame reactions often occurred in conjunction with the suicide attempt. Feelings of shame were accompanied by impulses to hide or flee, i.e., fear of seeking help or impulses to leave the hospital. The attempted suicide patients often experienced the initial encounter at the hospital as difficult. Having attempted suicide and survived was often perceived as yet another failure, in addition to the problems leading to the attempt. The attempted suicide patients were sensitive to the attitudes and behaviours of the personnel. Experiencing the personnel as kind, respectful, and nonjudgemental seemed to contribute to a relief from shame for some patients. Some respondents expressed that a tolerant and flexible atmosphere in the psychiatric ward, with low demands on the attempted suicide patient, helped them accept treatment and made them feel less ashamed for not living up to the expectations of everyday life. On the other hand, feeling too exposed to others or experiencing negative attitudes from the personnel seemed to contribute to an exacerbation of shame for some patients. Being aware of possible shame reactions after a suicide attempt might help caring personnel to understand and interact with attempted suicide patients in a way that could make it easier for these patients to accept and benefit from psychiatric care after a suicide attempt.     

Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients

AIMS: This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. METHODS: One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. RESULTS: Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. CONCLUSIONS: The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.     

Mechanistic models for myelosuppression

As myelosuppression is the dose-limiting toxicity for most chemotherapeutic drugs, modelers attempt to find relationships between drug and toxicity to optimize treatment. Mechanistic models, i.e. models based on physiology and pharmacology, are preferable over empirical models, as prior information can be utilized and as they generally are more reliable for extrapolations. To account for different dosing-regimens and possible schedule-dependent effects, the whole concentration–time profile should be used as input into the pharmacokinetic–pharmacodynamic model. It is also of importance to model the whole time course of myelosuppression to be able to predict both the degree and duration of toxicity as well as consecutive courses of therapy. A handful of (semi)-mechanistic pharmacokinetic–pharmacodynamic models with the above properties have been developed and are reviewed. Ideally, a model of myelosuppression should separate drug-specific parameters from system related parameters to be applicable across drugs and useful under different clinical settings. Introduction of mechanistic models of myelosuppression in the design and evaluation of clinical trials can guide in the decision of optimal sampling times, contribute to knowledge of optimal doses and treatment regimens at an earlier time point and identify sub-groups of patients at a high risk of myelosuppression.     

Cancer survival in Sweden 1960-1998--developments across four decades

This paper summarizes a comprehensive study of cancer survival in Sweden from 1960 to 1998. A total of 1021421 persons and 40 different cancer sites were included in the analyses. The main outcome measure is the relative survival rate (RSR) for different sites and follow-up times after diagnosis. The 10-year RSR for all sites combined has increased steadily-from 26.6% among men and 41.8% among women in the 1960s, to 44.6% (men) and 57.6% (women) in the 1990s. The expectation of life for a person diagnosed with cancer today is about 7 years longer than that of one diagnosed during the mid-1960s. About 3 years are gained due to changes in the relative distribution of various cancer types and about 4 years due to improved relative survival. During the 1990s substantial survival improvements were observed not only for uncommon types, such as testicular cancer, Hodgkin's lymphoma and some other haematologic malignancies, but also for cancer of the rectum, kidney and malignant melanoma. Survival for breast and cervical cancer also improved during the 1990s, but not that for pancreatic, liver or lung cancer.     

Are gadolinium-based contrast media really safer than iodinated media for digital subtraction angiography in patients with azotemia?

Gadolinium chelates, intended as intravenous contrast media for magnetic resonance imaging, have been regarded as nonnephrotoxic and recommended to replace iodinated contrast media in patients with azotemia who are undergoing digital subtraction angiography (DSA). High intraarterial doses (up to 220 mmol of gadodiamide) have been used, with a 40% incidence of nephropathy. The authors discourage the use of gadolinium for DSA for several reasons. (a) There exist no randomized studies comparing the nephrotoxic effects of gadolinium-based and iodinated media at equal-attenuating concentrations and doses. (b) Gadolinium-based media are hypertonic, a pathogenetic factor in contrast medium-induced nephropathy after renal angiography, with an osmolality two to seven times that of plasma. Iodinated media in concentrations that are equally attenuating with gadolinium-based media can be made isotonic. (c) In vitro measurements indicate that 0.5 mol/L gadolinium chelates are equally attenuating with 60-80 mg iodine per milliliter at the commonly used 70-90-kV range used for DSA. Thus, 50 mL of 0.5 mol/L gadolinium chelate ( approximately 0.3 mmol/kg in an 80-kg person) would be equally attenuating with a dose of 3-4 g of iodine in an iodinated medium (eg, 50 mL iohexol at 60-80 mg I/mL or 10-13 mL at 300 mg I/mL). (d) By combining these data on attenuation and results of toxicity studies in mice, the general toxicity of gadolinium chelates may be six to 25 times higher than that of equal-attenuating doses of iodinated media at 70-kV DSA. Thus, the authors believe that at equal-attenuating doses for DSA, modern iodinated contrast media should result in a lower toxic load on the body than with presently available gadolinium chelates.