Can sensation of cold hands predict Raynaud's phenomenon or paraesthesia?

Background: Raynaud's phenomenon and neurosensory symptoms are common after hand-arm vibration exposure. Knowledge of early signs of vibration injuries is needed. Aims: To investigate the risk of developing Raynaud's phenomenon and paraesthesia in relation to sensation of cold hands in a cohort of male employees at an engineering plant. Methods: We followed a cohort of male manual and office workers at an engineering plant in Sweden for 21 years. At baseline (1987 and 1992) and each follow-up (1992, 1997, 2002, 2008), we assessed sensation of cold, Raynaud's phenomenon and paraesthesia in the hands using questionnaires and measured vibration exposure. We calculated risk estimates with univariate and multiple logistic regression analyses and adjusted for vibration exposure and tobacco usage. Results: There were 241 study participants. During the study period, 21 individuals developed Raynaud's phenomenon and 43 developed paraesthesia. When adjusting the risk of developing Raynaud's phenomenon for vibration exposure and tobacco use, the odds ratios were between 6.0 and 6.3 (95% CI 2.2-17.0). We observed no increased risk for paraesthesia in relation to a sensation of cold hands. Conclusions: A sensation of cold hands was a risk factor for Raynaud's phenomenon. At the individual level, reporting a sensation of cold hands did not appear to be useful information to predict future development of Raynaud's phenomenon given a weak to moderate predictive value. For paraesthesia, the sensation of cold was not a risk factor and there was no predictive value at the individual level.

Relationships between work-related factors and musculoskeletal health with current and future work ability among male workers.

PURPOSE: The purpose was to increase job-specific knowledge about individual and work-related factors and their relationship with current and future work ability (WA). We studied cross-sectional relationships between mental demands, physical exertion during work, grip strength, musculoskeletal pain in the upper extremities and WA and the relationships between these variables and WA 11 years later. METHODS: We used a dataset of a prospective cohort study (1997-2008) among employees of an engineering plant (n = 157). The cohort was surveyed by means of tests and written questions on work demands, musculoskeletal health, WA score (WAS; 0-10), and mental and physical WA. Spearman correlation coefficients and logistic regression analysis were used. RESULTS: Among manual workers, we found weak correlations between grip strength and current and future physical WA. We did not find predictors for future poor WA among the manual workers. Among the office workers, we found that musculoskeletal pain was moderately and negatively related to current WAS and physical WA. More handgrip strength related to better future WAS and physical WA. Musculoskeletal pain (OR 1.67 p < 0.01) and lower handgrip strength (OR 0.91 p < 0.05) predicted future poor WA among office workers. CONCLUSIONS: Our results showed cross-sectional and longitudinal relationships between musculoskeletal health and work ability depending on occupation. However, the present implies that predicting work ability in the far future based on health surveillance data is rather difficult. Testing the musculoskeletal system (grip strength) and asking workers' about their musculoskeletal health seems relevant when monitoring work ability.

Neck pain combined with arm pain among professional drivers of forest machines and the association with whole-body vibration exposure.

The purpose of this study was to investigate the existence of neck pain and arm pain among professional forest machine drivers and to find out if pain were related to their whole-body vibration (WBV) exposure. A self-administered questionnaire was sent to 529 forest machine drivers in northern Sweden and the response was 63%. Two pain groups were formed; 1) neck pain; 2) neck pain combined with arm pain. From WBV exposure data (recent measurements made according to ISO 2631-1, available information from reports) and from the self-administered questionnaire, 14 various WBV exposure/dose measures were calculated for each driver. The prevalence of neck pain reported both for the previous 12 months and for the previous 7 d was 34% and more than half of them reported neck pain combined with pain in one or both arms. Analysis showed no significant association between neck pain and high WBV exposure; however, cases with neck pain more often experienced shocks and jolts in the vehicle as uncomfortable. There was no significant association between the 14 WBV measures and type of neck pain (neck pain vs. neck pain combined with arm pain). It seems as if characteristics of WBV exposure can explain neither existence nor the type of neck pain amongst professional drivers of forest machines. The logging industry is important for several industrialised countries. Drivers of forest machines frequently report neuromusculoskeletal pain from the neck. The type of neck pain is important for the decision of treatment modality and may be associated with exposure characteristics at work.

Thermal perception thresholds among young adults exposed to hand-transmitted vibration.

INTRODUCTION: Quantitative sensory testing assesses non-invasively the function of the sensory pathways from receptors to cortex. Studies of workers exposed to vibration support evidence that neuro-sensory hand-arm vibration syndrome also encompasses neuropathy of the small-diameter nerve fibres. OBJECTIVES: To assess the risk of disturbed thermal perception developing among young adults exposed to vibration and hand-intensive manual work. The aim also encompasses the study of alternative covariates in small-diameter nerve fibre neuropathy assessment. METHODS: This cross-sectional multi-centre study comprised 202 males and females from vocational school programs in auto mechanics, construction and catering. The testing included a baseline questionnaire, a clinical examination focusing on upper extremity disorders and quantitative somatosensory testing. Thermal perception thresholds were assessed, on both hands, second and fifth digits, using a modified Marstock method for warmth and cold. RESULTS: Reduced thermal perception sensitivity was found for digit II compared to digit V, for females compared to males, and between the two study centres. Subjects exposed to vibration at work showed reduced sensitivity to temperature compared to non-vibration exposed. In univariate analyses odds ratios of 1.06 (95% CI 1.006-1.118) and 1.02 (95% CI 0.971-1.078) for reduced perception to cold for the right and left hands, respectively, was found for vibration. This association was lost in multivariate analyses. The study centre was the strongest confounding influence. CONCLUSIONS: Sensitivity to temperature appears to be reduced despite the subjects short exposure-time and low exposure to vibration. The effect is small in relation to other confounding factors. A low agreement between the modalities indicates the need for separate tests for cold and warmth. Hand-side, age, stature, and BMI were not important for thermal perception but study centre, gender and choice of digit were. Conventional electro-diagnostic investigations are inadequate for evaluating the status of the small-fibre afferent systems leaving QST of thermal perception as the preferred diagnostic tool.

Effect of vibration magnitude, vibration spectrum and muscle tension on apparent mass and cross axis transfer functions during whole-body vibration exposure.

Twelve seated male subjects were exposed to 15 vibration conditions to investigate the nature and mechanisms of the non-linearity in biomechanical response. Subjects were exposed to three groups of stimuli: Group A comprised three repeats of random vertical vibration at 0.5, 1.0 and 1.5 ms(-2) r.m.s. with subjects sitting in a relaxed upright posture. Group B used the same vibration stimuli as Group A, but with subjects sitting in a 'tense' posture. Group C used vibration where the vibration spectrum was dominated by either low-frequency motion (2-7 Hz), high-frequency motion (7-20 Hz) or a 1.0 ms(-2) r.m.s. sinusoid at the frequency of the second peak in apparent mass (about 10-14 Hz) added to 0.5 ms(-2) r.m.s. random vibration. In the relaxed posture, frequencies of the primary peak in apparent mass decreased with increased vibration magnitude. In the tense posture, the extent of the non-linearity was reduced. For the low-frequency dominated stimulus, the primary peak frequency was lower than that for the high-frequency dominated stimulus indicating that the frequency of the primary peak in the apparent mass is dominated by the magnitude of the vibration encompassing the peak. Cross-axis transfer functions showed peaks of about 15-20% and 5% of the magnitudes of the peaks in the apparent mass for x- and y-direction transfer functions, respectively, in the relaxed posture. In the tense posture, cross-axis transfer functions reduced in magnitude with increased vibration, likely indicating a reduced fore-aft pitching of the body with increased tension, supporting the hypothesis that pitching contributes to the non-linearity in apparent mass.

Primary angioplasty and thrombolysis for acute myocardial infarction: an evidence summary.

Coronary angioplasty is being increasingly used as the primary treatment for patients with acute myocardial infarction, but controversy remains over its potential adoption in preference to thrombolysis as standard care. This report summarizes the published evidence on health outcomes after primary angioplasty compared with thrombolysis or no intervention for patients with acute myocardial infarction. The data tables presented provide the scientific groundwork to assist physicians and other policy-makers in deciding which interventions to provide for broad populations of patients.

Initial cost of primary angioplasty for acute myocardial infarction.

OBJECTIVES: We sought to evaluate the initial economic cost of primary angioplasty for acute myocardial infarction under varying assumptions about whether a cardiac catheterization laboratory exists, whether services are provided during night and weekend hours and how cardiovascular surgical backup is arranged. BACKGROUND: Primary angioplasty for acute myocardial infarction has resulted in clinical outcomes superior or equal to those obtained with thrombolysis in recent studies, but its future implementation depends greatly on its cost and cost-effectiveness. There is a gap in knowledge about the true economic costs of this procedure, and understanding costs under a variety of hypothetic scenarios is important in planning whether and how the procedure should be offered to broad groups of patients. METHODS: A generalizable spreadsheet model was constructed to calculate the cost of primary angioplasty at a single hospital with assumptions based on data from a large nonprofit health maintenance organization (Kaiser Permanente). The following baseline assumptions were made: 1) A total of 200 patients with myocardial infarction presented to the hospital each year; 2) primary angioplasty was offered for 10 years; 3) the hospital had a cardiac catheterization laboratory; 4) costs of night call for technical personnel and cardiovascular surgical backup were already covered. Other scenarios were modeled to represent different assumptions about existing resources. RESULTS: Under the baseline assumptions, primary angioplasty cost $1,597/procedure. If night call for technical personnel were a new expense, the average cost would be > or = $3,206. If a new cardiac catheterization laboratory needed to be built, costs would range from $3,866 to $14,339/procedure, depending on how cardiovascular surgical backup was provided. Results were sensitive to assumptions about the annual volume of myocardial infarctions, the number of years the procedure was offered and the costs of labor, construction and equipment. CONCLUSIONS: The initial cost of providing primary angioplasty for acute myocardial infarction varies greatly, depending on the setting in which it is provided. To provide information for clinical policy decisions, a cost-effectiveness model is needed that combines these initial costs with data on survival, quality of life and rates and costs of subsequent cardiac procedures.

Projected cost-effectiveness of primary angioplasty for acute myocardial infarction.

OBJECTIVES: This study sought to evaluate the cost-effectiveness of primary angioplasty for acute myocardial infarction under varying assumptions about effectiveness, existing facilities and staffing and volume of services. BACKGROUND: Primary angioplasty for acute myocardial infarction has reduced mortality in some studies, but its actual effectiveness may vary, and most U.S. hospitals do not have cardiac catheterization laboratories. Projections of cost-effectiveness in various settings are needed for decisions about adoption. METHODS: We created a decision analytic model to compare three policies: primary angioplasty, intravenous thrombolysis and no intervention. Probabilities of health outcomes were taken from randomized trials (base case efficacy assumptions) and community-based studies (effectiveness assumptions). The base case analysis assumed that a hospital with an existing laboratory with night/weekend staffing coverage admitted 200 patients with a myocardial infarction annually. In alternative scenarios, a new laboratory was built, and its capacity for elective procedures was either 1) needed or 2) redundant with existing laboratories. RESULTS: Under base case efficacy assumptions, primary angioplasty resulted in cost savings compared with thrombolysis and had a cost of $12,000/quality-adjusted life-year (QALY) saved compared with no intervention. In sensitivity analyses, when there was an existing cardiac catheterization laboratory at a hospital with > or = 200 patients with a myocardial infarction annually, primary angioplasty had a cost of < $30,000/QALY saved under a wide range of assumptions. However, the cost/QALY saved increased sharply under effectiveness assumptions when the hospital had < 150 patients with a myocardial infarction annually or when a redundant laboratory was built. CONCLUSIONS: At hospitals with an existing cardiac catheterization laboratory, primary angioplasty for acute myocardial infarction would be cost-effective relative to other medical interventions under a wide range of assumptions. The procedure's relative cost-ineffectiveness at low volumes or redundant laboratories supports regionalization of cardiac services in urban areas. However, approaches to overcoming competitive barriers and close monitoring of outcomes and costs will be needed.

Beta-blocker dosages and mortality after myocardial infarction: data from a large health maintenance organization.

BACKGROUND: Although long-term beta-blocker therapy has been found beneficial in patients after an acute myocardial infarction, these drugs are greatly underused by clinicians. Moreover, the dosages of beta-blockers used in randomized controlled trials appear to be much larger than those routinely prescribed. OBJECTIVE: To determine whether an association exists between the dosage of beta-blockers prescribed after a myocardial infarction and cardiac mortality. METHODS: We performed a retrospective cohort study of 1165 patients who survived an acute myocardial infarction from January 1, 1990, through December 31, 1992. These patients represent a subgroup of the 6851 patients hospitalized at northern California Kaiser Permanente hospitals. RESULTS: Of the 37.7% of patients prescribed beta-blocker therapy, 48.1% were treated with dosages less than 50% of the dosage found to be effective in preventing cardiac death in large randomized clinical trials (lower-dosage therapy). Compared with patients not receiving beta-blockers, those treated with lower-dosage therapy appeared to have a greater reduction in cardiovascular mortality (hazard ratio, 0.33; P=.009) than patients treated with a higher dosage (hazard ratio, 0.82; P=0.51), after adjustment for age, sex, race, disease severity, and comorbidities. CONCLUSIONS: The dosages of beta-blockers shown to be effective in randomized trials are not commonly used in clinical practice, and treatment with lower dosages of beta-blockers was associated with at least as great a reduction in mortality as treatment with higher dosages. This suggests that physicians who are reluctant to prescribe beta-blockers because of the relatively large dosages used in the large prospective clinical trials should be encouraged to prescribe smaller dosages.

Seated postural neck and trunk reactions to sideways perturbations with or without a cognitive task.

Driving on irregular terrain will expose the driver to sideways mechanical shocks or perturbations that may cause musculoskeletal problems. How a cognitive task, imposed on the driver, affects seated postural reactions during perturbations is unknown. The aim of the present study was to investigate seated postural reactions in the neck and trunk among healthy adults exposed to sideways perturbations with or without a cognitive task. Twenty-three healthy male subjects aged 19-36 years, were seated on a chair mounted on a motion system and randomly exposed to 20 sideways perturbations (at two peak accelerations 5.1 or 13.2m/s(2)) in two conditions: counting backwards or not. Kinematics were recorded for upper body segments using inertial measurement units attached to the body and electromyography (EMG) was recorded for four muscles bilaterally in the neck and trunk. Angular displacements (head, neck, trunk and pelvis) in the frontal plane, and EMG amplitude (normalised to maximum voluntary contractions, MVC) were analysed. The cognitive task provoked significantly larger angular displacements of the head, neck and trunk and significantly increased EMG mean amplitudes in the upper neck during deceleration, although 10% of MVC was never exceeded. A cognitive task seems to affect musculoskeletal reactions when exposed to sideways perturbations in a seated position.

Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. The Swedish Lung Cancer Study Group.

The aim of this randomised trial was to investigate the effect of induction chemotherapy before radiotherapy on survival in 302 patients with non-resectable squamous cell carcinoma of the lung. Radiotherapy, 56 Gy to the chest, was given to 154 patients and combined treatment, with chemotherapy preceding the radiotherapy, to 148 patients. Chemotherapy consisted of three courses of cisplatin (120 mg/m2) and etoposide (100 mg/m2 i.v. for 3 days) administered every fourth week. Median survival was 10.5 months in the radiotherapy arm and 11 months in the combined treatment arm. The 2-year survival rate was 17% in the radiotherapy arm and 21% in the combined treatment arm. Addition of chemotherapy seemed to significantly improve survival, according to the Cox multivariate analysis (P = 0.04), but as only a trend according to life-table analysis (P = 0.11). Chemotherapy also accomplished a trend towards improved local control (P = 0.08) and towards decreased metastatic disease (P = 0.10). 2 patients in the combined treatment arm, but none in the radiotherapy arm, died from toxicity. The conclusion was that the value of the chemotherapy used in this study was very modest, but the results strongly support further research for more efficient drugs and combinations.

Predictors of survival after coronary bypass grafting in patients with total occlusion of the left main coronary artery.

Twenty-three patients with angiographically documented total occlusion of the left main coronary artery were retrospectively identified. Statistical analysis suggests that poor right-to-left collaterals and the presence of concurrent significant right coronary artery disease were weakly associated with decreased survival after bypass surgery.

Responses of mechanoreceptive afferent units in the glabrous skin of the human hand to sinusoidal skin displacements.

The impulse responses to perpendicular sinusoidal skin displacements were recorded from 4 different types of mechanoreceptive different units innervating the glabrous skin of the human hand. The cycle responses, defined as the number of impulses evoked per sine wave cycle, were studied at a wide range of frequencies (0.5-400 Hz) and amplitudes (0.001-1mm). The rapidly adapting units (RA) were most easily excited at stimulus frequencies between 8 and 64 Hz, whereas the corresponding frequencies for the Pacinian units (PC) were above 64 Hz. However, at high stimulus amplitudes, the RA and the PC units showed quite similar response profiles within the range of frequencies tested. The sensitivities of the slowly adapting unit types (SA I and SA II) were greatest at lower frequencies. A characteristic finding for all 4 types of units was that the higher the amplitude, the lower the frequency at which the cycle response was maximal.

Sensitivity to edges of mechanoreceptive afferent units innervating the glabrous skin of the human head.

One type of rapidly adapting (RA) and one type of slowly adapting (SA I) mechanoreceptive unit innervating the glabrous skin area of the human hand have small and well defined receptive fields. Their responses to perpendicular sinusoidal skin displacements were measured when the field was completely covered by a flat contact surface and when the edge of the contact surface was placed over the field. It was found that the majority of the RA and SA I units exhibited stronger responses when the edge of the contactor was placed over the receptive field. This edge sensitivity, which was greatest for the SA I units, may be of particular importance in improving the spatial analysis of the edges of objects in contact with the skin during manual manipulation and exploration.

Local vibrations--mechanical impedance of the human hand's glabrous skin.

The mechanical point impedance has been studied in ten different areas of the glabrous skin of the human hand on three male and three female subjects within the frequency range of 20-10 000 Hz. For all tested areas the impedance decreased with increasing frequency down to a minimum value, corresponding to the natural frequency of the skin. After that, the mechanical impedance was directly proportional to the frequency. The highest natural frequency, about 200 Hz, was measured in the distal areas of the finger and the lowest, about 80 Hz, in the proximal areas of the palm (thenar). Small differences in internal damping were also showed to exist. A great amount of handheld tools used in industry have their maximum vibrational levels within the natural frequency range of the skin. In order to avoid adverse effects the skin's mechanical properties should therefore carefully be taken into consideration at designing vibrating tools.

Absorption of energy during vertical whole-body vibration exposure.

Absorbed power (PAbs) during exposure to vertical whole-body vibration in a sitting posture was measured on 15 male and 15 female subjects. Different experimental conditions were applied, such as vibration level (0.5-1.4 m s(-2)) and frequency (2-100 Hz), body weight (54-93 kg) and, relaxed and erected upper body positions. Results show that PAbs was strongly related to the frequency of the vibration, peaking within the range of 4-6 Hz. The peak was predominantly located in the lower end of this range for females and for the relaxed sitting position. PAbs increased with acceleration level and body weight. Almost a ten-fold increase in PAbs was observed at the critical frequency when the vibration exposure was raised from 0.5 to 1.4 m s(-2). If risk assessment is based on the assumption that the amount of PAbs, independent of the frequency of the vibration, indicates a hazard, then the ISO-standard 2631 under- and overestimates the risk at frequencies below and above about 6 Hz, respectively. The results also indicate a need for differentiated guidelines for females and males. Many types of vehicles produce whole-body vibration with frequencies which coincide with the range where the highest PAbs was observed. PAbs is a 'new' concept for measurement of whole-body vibration exposure. Although not yet thoroughly evaluated, this measure may be a better quantity for risk assessment than those specified in ISO 2631 since it also takes the dynamic force applied to the human body into account.

The apparent mass of the human body exposed to non-orthogonal horizontal vibration.

Apparent masses of 15 male and 15 female subjects have been measured during exposure to various directions of horizontal vibration. Twenty vibration conditions were used in the experiment. In each of five directions (0, 22.5, 45, 67.5 and 90 degrees to the mid-sagittal plane) subjects were exposed to random vibration in the frequency range of 1.5-20 Hz at 0.25, 0.5 and 1.0 m s(-2) r.m.s. The five remaining conditions were selected to give measurements whereby the magnitude of the x-component of the vibration was fixed and the gamma-component changed and vice-versa. Two peaks were observed in the apparent masses. The first peak occurred at about 3 Hz and reduced in frequency with increases in vibration magnitude. The frequency of the first peak also reduced as the direction of vibration changed from 0 to 90 degrees. The magnitude of the peak increased as the vibration magnitude and direction increased. The second peak occurred at about 5 Hz and decreased in both frequency and magnitude with increases in vibration magnitude. There was no change in the frequency of the second peak with vibration direction, although the magnitude of the peak decreased as the angle of vibration to the mid-sagittal plane increased. Increasing the magnitude of the x-component of vibration whilst using a fixed y-component changed the magnitude of the first peak but did not change the frequency of the first or any characteristics of the second peak. In contrast, increasing the y-component of vibration whilst using a fixed x-component changed the frequencies and magnitudes of both peaks. Predictions of the response at 45 degrees by applying the principle of superposition to data measured at 0 and 90 degrees showed that the response of the body with direction was not linear. This implies that the apparent mass in non-orthogonal axes cannot be predicted from the apparent masses measured in orthogonal directions.

Responses of mechanoreceptive afferent units in the glabrous skin of the human hand to vibration.

The impulse response to vibration (0.5-400 Hz, 0.001-1.0 mm) was recorded from single mechanoreceptive afferents innervating the glabrous skin of the human hand. Needle electrodes inserted into the median nerve were used for the recording. The four types of mechanoreceptive afferents (FA I, FA II, SA I, and SA II) exhibited different response characteristics. Fast adapting units were the most easily excited at frequencies between about 5 to 50 Hz (FA I) and above about 50 Hz (FA II). The sensitivity of the slowly adapting units (SA I and SA II) was greatest at lower frequencies. Unit thresholds at 2, 20, and 200 Hz were measured before and after 2 min of powerful vibration exposure. Corresponding psychophysical thresholds were also measured during the recording of responses from single units. An acute but temporary depression in sensitivity occurred in the FA I, FA II, and SA I units as a consequence of the exposure. The magnitude and the time courses of the recovery of the encountered unit threshold shifts were approximately the same as those for the corresponding psychophysical threshold shifts. It was concluded that acute impairments of the tactile sensibility caused by vibration exposure, as observed in psychophysical studies, can probably be explained by an influence on the excitability of the tactile units.

Vibrotactile perception thresholds as determined by two different devices in a working population.

OBJECTIVES: The purpose of this study was to investigate whether two devices for measuring vibrotactile perception thresholds produced similar results on an individual basis and to compare the thresholds in the presence or absence of sensorineural hand symptoms and vibration exposure. METHODS: Vibrotactile perception thresholds were measured with a vibrameter and a tactilometer in 178 men. The tactilometer uses seven discrete frequencies from 8 to 500 Hz, and the vibrameter uses one frequency (100 Hz). Agreement was assessed from the correlations and from a comparison of subjects who had thresholds above the upper quartile of each device as to the presence of sensorineural hand symptoms and occupational vibration exposure. RESULTS: The correlation between the vibrameter and the tactilometer (125 Hz) was 0.59. The agreement between the vibrameter and the tactilometer (63 Hz), when the upper quartile was used as a limit, had a sensitivity of 0.56 and a specificity of 0.85. The sensitivity and specificity for the agreement with symptoms were 0.44 and 0.79, respectively, for the tactilometer and 0.40 and 0.78, respectively, for the vibrameter. The indices combined from the different frequencies of the tactilometer did not improve the agreement. CONCLUSIONS: Some of the discrepancy between the measurement of the vibrameter and tactilometer can be explained by differences in the equipment, the measurement procedures, and the examiner, combined with high inter-and intraindividual variability. Neither of the two devices was superior when the results were compared as to the occurrence of hand symptoms and vibration exposure. As evaluated in this study vibrotactile perception threshold has a restricted value for screening and diagnostic purposes on an individual basis.

Modeling the evolution of the human mitochondrial genome.

Mitochondrial DNA data have been used extensively to study evolution and early human origins. These applications require estimates of the rate at which nucleotide substitutions occur in the DNA sequence. We consider the problem of estimating substitution rates in the presence of site-to-site rate variation. A coalescent model is presented that allows for different substitution rates for purines and pyrimidines, as well as more detailed models that allow fast and slow rates within each of the purine and pyrimidine classes. A method for estimating such rates is presented. Even for these simple models of site heterogeneity, there are, typically, insufficient data to obtain reliable estimates of site-specific substitution rates. However, estimates of the average rate across all sites appear to be relatively stable even in the presence of site heterogeneity. Simulations of models with site-to-site variation in mutation rate show that hypervariable sites can produce peaks in the pairwise difference curves that have previously been attributed to population dynamics.