Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study.

OBJECTIVE: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). PARTICIPANTS AND METHODS: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose D-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient's health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. RESULTS: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40-0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15-0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9-14.2 (0.86-1.77 effect size) on the mRSS and 0.21-0.55 (0.32-0.83 effect size) on the HAQ-DI score. CONCLUSION: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.

Analgesic and disease modifying effects of interferential current in psoriatic arthritis.

Interferential current (IFC) was suggested to improve the skin manifestations of psoriasis vulgaris, possibly by enhancing the intracellular concentration of cyclic AMP. We assessed the efficacy of IFC on psoriatic arthritis (PsA). Nine consecutive patients were analyzed at baseline and after 16 weeks of IFC therapy. Bipolar IFC was applied twice daily to hands, feet plus all affected joints. IFC improved SF-36 assessed body pain, but not other SF-36 subscales. Morning stiffness, tender joint counts, and physician assessed disease activity improved. In contrast, visual analogue scale assessed pain, CRP and ESR measurements were unchanged. MRI of the most affected hand or foot documented a tendency towards worsened tendinitis, soft tissue swelling, and new joint space narrowing and erosions. Bone scintigraphy showed a trend towards deterioration. New joints became inflamed within treated sites. Thus IFC has analgesic effects in PsA, but does not have a satisfactory disease modifying effect.

The Disability Index of the Health Assessment Questionnaire is a predictor and correlate of outcome in the high-dose versus low-dose penicillamine in systemic sclerosis trial.

OBJECTIVE: To explore the clinical implications of a score of > or =1.0 on the Disability Index of the Health Assessment Questionnaire (HAQ DI) at the first patient visit, and to examine the implications of improvement in HAQ DI score over 2 years in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. METHODS: SSc skin and visceral involvement was assessed in 134 SSc patients with diffuse scleroderma (mean +/- SD disease duration of 10 +/- 4 months) when they entered a multicenter drug trial and again 2 years later. Mortality and the occurrence of scleroderma renal crisis were assessed for a mean +/- SD of 4.0 +/- 1.1 years. Logistic and linear regression analyses were used to examine the relationship of the baseline HAQ DI score to morbidity, mortality, and visceral involvement, as well as the relationship of changes in the HAQ DI score to changes in physical examination, laboratory, and functional variables over 2 years. RESULTS: A baseline HAQ DI score of > or =1.0 was predictive of mortality (odds ratio 3.22, 95% confidence interval 1.097-9.468) over 4 years. Multivariate linear regression demonstrated that a model which included the erythrocyte sedimentation rate at baseline (P = 0.005) and changes at 2 years in the swollen joint count (P = 0.002), total skin score (P = 0.005), and white blood cell count (P = 0.005) best explained the change in HAQ DI score over 2 years (R2 = 0.528). The HAQ DI score and total skin score at baseline were highly correlated (correlation coefficient 0.368), as were changes in the HAQ DI score and the total skin score over 2 years (correlation coefficient 0.492). Although the HAQ DI score was heavily influenced by hand dysfunction at baseline and at 2 years, improvement (reduction) in the HAQ DI score over 2 years was related to factors other than hand dysfunction. CONCLUSION: A baseline HAQ DI score of > or =1.0 predicted mortality over 4 years. Improvement in the HAQ DI score in these patients with diffuse scleroderma was associated with improvement in skin thickening, hand function, oral aperture, lung function, signs of arthritis, serum creatinine level, and the investigator's global assessment of improvement. The HAQ DI is a self-administered questionnaire that SSc patients can complete easily and rapidly and that gives the practicing physician important information about prognosis, patient status, and changes in disease course over time.

Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial.

OBJECTIVE: To study the clinical implications of a skin thickness score > or =20 at first visit and of softening of sclerodermatous skin in a cohort of systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma. METHODS: Skin and visceral involvement were assessed in 134 SSc patients with diffuse scleroderma (mean +/- SD duration of SSc 10 +/- 4 months) as they entered a multicenter drug trial and again at 2 years of followup. Advent of mortality and scleroderma renal crisis (SRC) were assessed during a followup of 4.0 +/- 1.1 years (mean +/- SD). Logistic and linear regression were used to examine the relationship of baseline skin score to morbidity, mortality, and visceral involvement and the relationship of changes in skin score to changes in physical examination, laboratory, and functional variables over 2 years. RESULTS: A baseline skin score > or =20 was associated with heart involvement at baseline (odds ratio [OR] 3.10, 95% confidence interval [95% CI] 1.25-7.70) and was predictive of mortality (OR 3.59, 95% CI 1.23-10.55) and SRC (OR 10.00, 95% CI 2.21-45.91) over 4 years. Multivariate linear regression demonstrated that a model with skin score at baseline (P = 0.0078) and changes in large joint contractures (P = 0.0072), tender joint counts (P = 0.0119), handspread (P = 0.0242), and Health Assessment Questionnaire disability index (HAQ-DI) (P = 0.0244) explained the change in skin score over 2 years (R2 = 0.567). Multivariate logistic regression demonstrated that the investigator's global assessment of improvement was best explained by a model with skin score and HAQ-DI (R2 = 0.455). CONCLUSION: A baseline skin score > or =20 was associated with heart involvement at baseline and predicted mortality and SRC over the subsequent 4 years. Improvement in skin score in these patients with diffuse cutaneous scleroderma was associated with improvement in hand function, inflammatory indices, joint contractures, arthritis signs, overall functional ability, and the examining investigator's global assessment of improvement.

Bending and fracture of compact circumferential and osteonal lamellar bone of the baboon tibia.

Lamellar bone is common among primates, either in the form of extended planar circumferential arrays, or as cylindrically shaped osteons. Osteonal bone generally replaces circumferential lamellar bone with time, and it is therefore of much interest to compare the mechanical properties and fracture behavior of these two forms of lamellar bone. This is, however, difficult as natural specimens of circumferential lamellar bone large enough for standard mechanical tests are not available. We found that as a result of treatment with large doses of alendronate, the lateral sides of the diaphyses of baboon tibia contained fairly extensive regions of circumferential lamellar bone, the structure of which appears to be indistinguishable from untreated lamellar bone. Three-point bending tests were used to determine the elastic and ultimate properties of almost pure circumferential lamellar bone and osteonal bone in four different orientations relative to the tibia long axis. After taking into account the differences in porosity and extent of mineralization of the two bone types, the flexural modulus, bending strength, fracture strain and nominal work-to-fracture properties were similar for the same orientations, with some exceptions. This implies that it is the lamellar structure itself that is mainly responsible for these mechanical properties. The fracture behavior and morphologies of the fracture surfaces varied significantly with orientation in both types of bone. This is related to the microstructure of lamellar bone. Osteonal bone exhibited quite different damage-related behavior during fracture as compared to circumferential lamellar bone. Following fracture the two halves of osteonal bone remained attached whereas in circumferential lamellar bone they separated. These differences could well provide significant adaptive advantages to osteonal bone function.

Correlates of the disability index of the health assessment questionnaire: a measure of functional impairment in systemic sclerosis.

OBJECTIVE: To evaluate functional impairment in systemic sclerosis (SSc) patients with diffuse cutaneous scleroderma at the time of entry into a trial of a therapeutic intervention (D-penicillamine). METHODS: The 20-item Disability Index of the Health Assessment Questionnaire (HAQ-DI) was administered to 134 patients as they entered a multicenter trial of high-dose versus low-dose D-penicillamine. All patients had diffuse SSc of < 18 months' duration. SSc patients who had severe organ system involvement and recent renal crisis and who were receiving prednisone > 10 mg/day were excluded from entry. Logistic regression modeling was used to examine the relationship of HAQ-DI scores to SSc skin and organ system involvement. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to estimate effects. RESULTS: The mean (+/-SD) HAQ-DI score at entry was 1.04 +/- 0.67. Fifty-three percent of patients had HAQ-DI scores > or = 1.0 (signifying moderate-to-severe functional impairment). Multivariate logistic regression demonstrated that impaired fist closure > or = 23 mm (OR 4.24, 95% CI 1.68-10.70), reduced handspread < or = 175 mm (OR 4.5, 95% CI 1.80-11.24), joint tenderness count > or = 1.0 (OR 2.93, 95% CI 1.16-7.40), age > or = 43 years (OR 2.44, 95% CI 1.01-5.95), platelet count > or = 330,000/mm3 (OR 2.30, 95% CI 0.96-5.57), and female sex (OR 2.43, 95% CI 0.77-7.73) were the most important correlates of HAQ-DI scores > or = 1.0. CONCLUSION: Increased HAQ-DI scores at baseline were correlated with reduced fist closure, reduced hand-spread, elevated platelet count, presence of tender joints, older age, and female sex. The most important contributor to functional impairment was hand dysfunction. Even within the first 18 months after SSc onset, moderate-severe functional impairment (HAQ-DI scores > or = 1.0) was frequent (53%) in this group of diffuse SSc patients. In early diffuse SSc, the self-administered HAQ-DI is therefore a valuable assessment of function that correlates with objective physical and laboratory measures of SSc disease involvement. Abnormal HAQ-DI scores may support patient claims of functional impairment, help to focus physician attention on implementing measures to reduce functional impairment, and be useful in reflecting the disease course over time.

High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial.

OBJECTIVE: To test the hypothesis that systemic sclerosis (SSc) patients taking high-dose D-penicillamine (D-Pen) would have greater softening of skin, lower frequency of renal crisis, and better survival than patients taking low-dose D-Pen. METHODS: Seventeen centers enrolled 134 SSc patients with early (< or =18 months) diffuse cutaneous scleroderma into a 2-year, double-blind, randomized comparison of high-dose D-Pen (750-1,000 mg/day) versus low-dose D-Pen (125 mg every other day). All 134 patients were followed up for a mean+/-SD of 4.0+/-1.1 years to assess the frequencies of new-onset scleroderma renal crisis (SRC) and mortality. RESULTS: Sixty-eight patients completed 24 months of drug treatment. The course of the modified Rodnan skin thickness score in the 32 high-dose and the 36 low-dose D-Pen completers was not different at 24 months: the skin score dropped 4.8+/-10.3 (mean+/-SD) units in the high-dose group and 6.9+/-8.4 units in the low-dose group (P = 0.384 by t-test; favoring low-dose D-Pen) from 20.4+/-10.3 in the high-dose and 19.9+/-6.6 in the low-dose D-Pen group at study entry. The incidences of SRC and mortality were not different (P > 0.38 by Cox proportional hazards and by chi-square test) in the 66 high-dose patients (8 developed SRC and 8 died) compared with the 68 low-dose patients (10 developed SRC and 12 died). Of the 20 adverse event-related withdrawals, 80% occurred in the high-dose D-Pen group. CONCLUSION: The course of the skin score and the frequencies of SRC and mortality in the high-dose D-Pen group were not different from those in the low-dose D-Pen group. Eighty percent of the adverse event-related withdrawals occurred in the high-dose D-Pen patients. Although this study cannot answer the question of whether low-dose D-Pen is effective, it does suggest that there is no advantage to using D-Pen in doses higher than 125 every other day.

Pattern recognition and interpretation of electromyogram data from cat jaw muscle.

This study investigates the effect of emotional behavior on the masseteric muscle EMG response patterns. Two experimental protocols are utilized: (1) does not elicit emotional behavior (stick chewing) and (2) elicits emotional behavior (hypothalamic stimulation). The Karhunen-Loève transform is used to compute features which exactly represent the correlated patterns of mean-zero observations, with data compression and noise immunity. Using nonparametric tests, it is found that the populations of biting and hissing features are significantly different (p < 0.05), with increased statistical significance as the size of the training set is increased. No statistically significant difference is seen in a test of the two biting populations.

Electromyographic activity in the masseter muscle resulting from stimulation of hypothalamic behavioral sites in the cat.

This study examined the relationship between hypothalamically elicited emotional behaviors and electromyographic activity in the masseter muscle of the cat. Electromyographic amplitudes resulting from stimulation at hypothalamic sites at which affective defense and quiet biting attack behaviors were elicited were compared with those recorded during stick biting that simulated mastication. The electromyographic activity elicited by hypothalamic stimulation was greater than that found from stick biting for all behavioral sites. At control sites, from which no behavior could be elicited, the electromyographic activity associated with stick biting exceeded that observed from the hypothalamic sites. These findings suggest a relationship between hypothalamically elicited behaviors and increased levels of jaw muscle activity.

Enkephalinergic involvement in periaqueductal gray control of hypothalamically elicited predatory attack in the cat.

The effects of central infusion of naloxone into the midbrain periaqueductal gray (PAG) upon predatory attack behavior in the cat were studied in 12 cats. Initially, quiet biting attack was elicited by electrical stimulation of sites within the lateral hypothalamus using monopolar electrodes. Then cannula-electrodes were implanted into sites within the PAG from which electrical stimulation facilitated or suppressed the attack response. Following identification of modulatory sites within the PAG, naloxone (1.0 micrograms/0.5 microliter) was microinjected into those sites and the effects upon hypothalamically elicited attack were assessed. At nine of twelve sites in the PAG where suppression was obtained, administration of naloxone served to block those effects. Similarly, at six of eight facilitatory sites within the PAG, naloxone also blocked the modulatory effects of PAG stimulation. However, vehicle (isotonic saline) alone did not alter the modulatory effects of PAG stimulation. Administration of DAME (250 ng/0.3 microliter) into PAG modulatory sites in four cats, two which facilitated and two that suppressed the attack response, reversed the effects of naloxone at these sites. These results demonstrate that opioid peptides within the PAG play a complex role in the expression of predatory attack behavior in the cat.

A [14C]2-deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. IV. A pathway from the prefrontal cortical-medial thalamic system to the hypothalamus.

The present study utilized the [14C]2-deoxyglucose (2-DG) cell labeling procedure to characterize a functional pathway from the prefrontal cortex (Pfc) and mediodorsal thalamic nucleus (MD) to the hypothalamus. Rats were injected with 2-DG prior to a 45 min experimental paradigm consisting of alternating 30 s on-off periods of electrical brain stimulation. Standard procedures were utilized for the removal and processing of brain tissue for X-ray autoradiography. In the first phase of this study, stimulation applied to the prefrontal cortex generally yielded a pattern of 2-DG distribution consistent with the findings of classical anatomical studies. Stimulation of the dorsomedial and ventromedial prefrontal cortex or the infralimbic cortex produced the most effective activation of the diencephalon. This activation was primarily limited to MD, with no involvement of any region of the hypothalamus. In the second phase of this study, brain regions activated following stimulation of sites along the rostro-caudal axis of MD were examined. Stimulation of MD resulted in the activation of the nucleus reuniens and other midline and non-specific thalamic nuclei. Stimulation of this nucleus also activated the ventromedial thalamic nucleus, medial aspects of the nucleus accumbens and the medial and sulcal prefrontal cortices. Again, in each of these cases, labeling within any region of the hypothalamus could not be detected. Since MD stimulation activated the midline thalamus, and the nucleus reuniens in particular, the last phase of this experiment involved stimulation of the nucleus reuniens in order to determine the source of medial thalamic inputs to the hypothalamus. Stimulation of the nucleus reuniens activated fibers which were distributed to both the medial and lateral hypothalamus. In addition, stimulation also activated the descending periventricular system, which could be followed to the level of the midbrain central gray and such limbic structures as the hippocampal formation, septal area, amygdala and prefrontal cortex. These findings indicate that Pfc-MD activation of the hypothalamus is achieved indirectly via interneurons within the nucleus reuniens.

A 14C-2-deoxyglucose analysis of the neural pathways of the limbic forebrain in the rat: II. The hypothalamus.

An attempt was made to characterize the nature of the functional organization of the hypothalamus by observing the patterns of uptake of 14C-2-deoxyglucose (2DG) following electrical stimulation of different regions within the preoptico-hypothalamus in the rat. The experimental paradigm consisted of electrical brain stimulation delivered continuously for periods of 30 sec on and 30 sec off for 45 minutes following injection of 2DG. Brains were removed and processed for autoradiography. Activation of the medial forebrain bundle was noted following stimulation of the nucleus accumbens and lateral preoptico-hypothalamus. Activated fibers could be followed only in a caudal direction through the medial forebrain bundle and into the ventral tegmental area as a result of nucleus accumbens stimulation. Stimulation of the lateral preoptic region or of the anterior half of lateral hypothalamus produced activation of the lateral septal nucleus, lateral habenular nucleus, perifornical region, midline thalamus and ventral tegmental area. Since stimulation of the perifornical hypothalamus significantly activated the rostro-caudal extent of the midbrain cental gray, it is suggested that impulses from the lateral hypothalamus reach the lower brainstem via its connections with the perifornical hypothalamus. Ventromedial hypothalamic stimulation activated only the lateral septal nucleus, cortico-medial amygdala and medial preoptico-hypothalamus, while medial preoptico-hypothalamic stimulation resulted in increased 2DG uptake in the midbrain central gray, thus suggesting that medial hypothalamic impulses reach the brainstem by first ascending to the level of the preoptico-hypothalamus. Mammillary body stimulation orthodromically activated fibers in the mammillothalamic and mammillotegmental tracts and antidromically fibers in the fornix for a short distance.

An analysis of the efferent connections of the septal area in the cat.

The neuroanatomical organization of the efferent connections of the septal area in the cat was analyzed by the use of anterograde ([3H]leucine radioautography) and retrograde (horseradish peroxidase histochemistry) tracing techniques. The results indicate that the lateral septal nucleus projects to the nuclei of the diagonal band, preoptic area, lateral hypothalamus, and supramammillary region. The projections of the septofimbrial nucleus supply the nuclei of the diagonal band and the medial habenular nucleus. Projection targets of the vertical limb of the diagonal band are widespread and include the preoptic area, lateral hypothalamus, anterior limbic cortex, amygdala, medial habenular nucleus, interpeduncular nucleus and hippocampal formation. The projection from the vertical limb to the hippocampal formation is organized in a topographical manner in such a fashion that cells positioned near the midline project to the dorsal hippocampus and adjoining subicular cortex while fibers originating from cells situated more laterally project to more ventral parts of the hippocampal formation. In general, the projections from the horizontal limb were similar to those from the vertical limb, but several differences were noted. Fibers arising from the horizontal limb are distributed to the ventral tegmental area and interpeduncular nucleus but this region seems to lack a projection to either the habenular complex or to the ventral aspect of the hippocampal formation. Fibers arising from the bed nucleus of the anterior commissure are distributed to the preoptic region, lateral hypothalamus, supramammillary region, posterior aspect of the medial mammillary nucleus and lateral habenular nucleus.