[Analyses of the risk factors for the progression of primary antiphospholipid syndrome to systemic lupus erythematosus].

Objectives: Analyze the clinical characteristics of patients with primary antiphospholipid syndrome (PAPS) progressing to systemic lupus erythematosus (SLE).Explore the risk factors for the progression from PAPS to SLE. Methods: The clinical data of 262 patients with PAPS enrolled in Peking Union Medical College Hospital from February 2005 to September 2021 were evaluated. Assessments included demographic data, clinical manifestations, laboratory tests (serum levels of complement, anti-nuclear antibodies, anti-double-stranded DNA antibodies), treatment, and outcomes. Kaplan-Meier analysis was used to calculate the prevalence of SLE in patients with PAPS. Univariate Cox regression analysis was employed to identify the risk factors for PAPS progressing to SLE. Results: Among 262 patients with PAPS, 249 had PAPS (PAPS group) and 13 progressed to SLE (5.0%) (PAPS-SLE group). Univariate Cox regression analysis indicated that cardiac valve disease (HR=6.360), positive anti-double-stranded DNA antibodies (HR=7.203), low level of complement C3 (HR=25.715), and low level of complement C4 (HR=10.466) were risk factors for the progression of PAPS to SLE, whereas arterial thrombotic events (HR=0.109) were protective factors (P<0.05 for all). Kaplan-Meier analysis showed that the prevalence of SLE in patients suffering from PAPS with a disease course>10 years was 9%-15%. Hydroxychloroquine treatment had no effect on the occurrence of SLE in patients with PAPS (HR=0.753, 95%CI 0.231-2.450, P=0.638). Patients with≥2 risk factors had a significantly higher prevalence of SLE compared with those with no or one risk factor (13-year cumulative prevalence of SLE 48.7% vs. 0 vs. 6.2%, P<0.001 for both). Conclusions: PAPS may progress to SLE in some patients. Early onset, cardiac-valve disease, positive anti-dsDNA antibody, and low levels of complement are risk factors for the progression of PAPS to SLE (especially in patients with≥2 risk factors). Whether application of hydroxychloroquine can delay this transition has yet to be demonstrated.

[Progressive necrosis of lipid: A case report].

A 61-year-old woman was referred to our department with a 11-year-erythra. In the anterior tibia of both lower extremities, we could see large dark red infiltrating erythema, waxy luster, clear boundary, slight central atrophy, depression and capillary dilatation. He was diagnosed with "dermatitis contusiformis" in local hospitals, but the treatment of traditional Chinese medicine and external drugs was not effective. She had normal laboratory findings for blood routine test, biochemical indexes, C reactive protein(CRP) and erythrocyte sedimentation rate(ESR)．Furthermore, autoimmune antibodies were all negative. The skin pathology showed degeneration and necrosis of collagen fibers, chronic granulomatous inflammation in the dermis, and there were more acute and chronic inflammatory cell infiltration around the small vessels and in the wall of the tube. We eventually diagnosed it as necrobiosis lipoidica (NL) according to the history, erythra morphology and skin pathology. After treatment of low dose hormone and thalidomide for 1 year, the color and range of skin lesions gradually alleviated. NL was a rare chronic granulomatous inflammatory disease. There appeared to be a predominance in females. The incidence of NL was higher in patients with diabetes mellitus, although this asscoiation was currently questioned. NL might also be connected with autoimmune diseases, such as rheumatoid arthritis, sarcoidosis, ulcerative colitis and Crohn's disease. The pathological changes of the tissue were mainly in the dermis, including necrotic type, granulomatous type or mixed type. NL typically presented on the pretibial surface of lower extremities. Less typical locations included the face, scalp, vulva and upper limbs. Leisions usually began with small papules and nodules that gradually infiltrated into brownyellow patches and developed central wax-like atrophy. The diagnosis is often based on clinical examination and skin biopsy. NL is rare and easy to be misdiagnosed. For rheumatologists, we should carefully compare with the nodular erythema, the microscopic polyangitis and allergic purpura. It is significant for differential diagnosis to perform skin biopsy. Lacking of randomized controlled trials, no specific treatment has proven to be the gold standard. First-line therapy mainly consists of intralesional and systemic corticosteriods. Additionally, other reported treatment options include immunomodulator, biological agent, antiplatelet aggregation drug and plateletrich plasma. These patients need long term follow up continuously for progression of the disease, ulcerations, and possibility of malignant tranformation.

Arousal and the pupil: why diazepam-induced sedation is not accompanied by miosis.

RATIONALE: There is a close relationship between arousal and pupil diameter, decrease in the level of arousal being accompanied by constriction of the pupil (miosis), probably reflecting the attenuation of sympathetic outflow as sedation sets in. Paradoxically, sedation induced by benzodiazepines is not accompanied by miosis. OBJECTIVE: The objective of this study was to examine the hypothesis that diazepam may attenuate both the sympathetic and the opposing parasympathetic outflow to the iris, which may mask the miosis. Dapiprazole (sympatholytic) and tropicamide (parasympatholytic) were applied topically, together with the cold pressor test (CPT), to manipulate the sympathetic/parasympathetic balance. MATERIALS AND METHODS: Sixteen healthy male volunteers participated in four weekly sessions according to a balanced double-blind protocol. Diazepam 10 mg (two sessions) and placebo (two sessions), associated with either 0.01% tropicamide or 0.5% dapiprazole eyedrops, were administered orally. Pupil diameter, light and darkness reflexes and pupillary sleepiness waves were recorded with infrared video pupillometry, alertness was measured by critical flicker fusion frequency (CFFF) and visual analogue scales (VAS), blood pressure and heart rate by conventional methods. CPT was applied after post-treatment testing. Data were analysed by analysis of variance, with multiple comparisons. RESULTS: Diazepam caused sedation (reduction in VAS alertness scores and CFFF, increase in sleepiness waves), dapiprazole had a sympatholytic and tropicamide a parasympatholytic effect on the pupil. Diazepam had no effect on pupil diameter and reflexes or their modifications by the antagonists. CPT increased pupil diameter, blood pressure and heart rate, and the increase only in systolic blood pressure was attenuated by diazepam. CONCLUSIONS: Diazepam-induced sedation is not accompanied by any change in either the sympathetic or parasympathetic influence on the iris.

Diazepam-induced disruption of classically-conditioned fear-potentiation of late-latency auditory evoked potentials is prevented by flumazenil given before, but not after, CS/US pairing.

Classical fear conditioning involves pairing a neutral conditional stimulus (CS) with an aversive unconditional stimulus (US). Subsequent presentation of the CS alone induces fear responses. Acquisition of conditioned fear is thought to involve learning of the CS/US association, followed by memory consolidation. Recently we reported that the N1/P2 auditory evoked potential was enhanced by fear conditioning in humans. Diazepam 10 mg, given before CS/US pairing, prevented subsequent expression of fear potentiation when the response was elicited, 1 week later, in the presence of the CS. In this experiment, we examined whether this effect of diazepam was caused by disruption of the formation of CS/US associations or by disruption of consolidation. The benzodiazepine antagonist flumazenil was used to block the effect of diazepam either during the association period or during subsequent consolidation. Forty-two male volunteers (18-35 years) participated in two sessions separated by 7 days. In Session One, they ingested diazepam 10 mg or placebo: 60 minutes later they received flumazenil 1 mg or saline intravenously (i.v.). Then they received 20 presentations of a light (CS), 50% of which terminated with electric shock (US). This was followed by a second infusion of flumazenil or saline. Subjects received placebo/saline/saline (Group 1), diazepam/saline/saline (Group 2), diazepam/flumazenil/saline (Group 3) and diazepam/saline/flumazenil (Group 4). In Session Two, the CS was presented without the US; 50% of CS presentations terminated with a sound pulse; an equal number of sound pulses were presented without the CS. Auditory evoked potentials were recorded at Cz. In Session Two, CS presentation enhanced the auditory N1/P2 potential in placebo-treated subjects (Group 1). This enhancement was prevented by diazepam (Group 2). Flumazenil reversed diazepam's effect on fear potentiation if it was administered before conditioning (Group 3), but not if it was administered afterwards (Group 4). The results confirm that diazepam prevents the acquisition of fear conditioning in humans, and suggest that it disrupts the formation of CS/US associations, rather than the consolidation of fear memory.

Comparison of diphenhydramine and modafinil on arousal and autonomic functions in healthy volunteers.

Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.

Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers.

RATIONALE: In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D(2)/D(3) autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger-Westphal nucleus (via a putative meso-pupillomotor pathway). OBJECTIVES: We investigated the hypothesis that amisulpride, a D(2)/D(3) receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions. MATERIALS AND METHODS: Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA. RESULTS: Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels. CONCLUSIONS: The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D(2)/D(3) receptors on VTA neurones and in the tuberoinfundibular system.

Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers.

The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.

Why patients with Alzheimer's disease may show increased sensitivity to tropicamide eye drops: role of locus coeruleus.

RATIONALE: Patients suffering from Alzheimer's disease (AD) may show increased sensitivity to tropicamide, a muscarinic cholinoceptor antagonist. AD is associated with a severe loss of noradrenergic neurones in the locus coeruleus (LC), which can be "switched off" experimentally by the alpha(2)-adrenoceptor agonist clonidine. The possibility arises that increased pupillary sensitivity to tropicamide in AD may be due to diminished LC activity. OBJECTIVE: To examine the hypothesis that clonidine may potentiate tropicamide-evoked mydriasis. MATERIALS AND METHODS: Sixteen healthy male volunteers participated in two experimental sessions (0.2 mg clonidine or placebo) conducted 1 week apart. In each session tropicamide (0.01% 10 microl x 2) was applied to the left eye and artificial tear (10 microl x 2) was applied to the right eye. Pupillary functions (resting pupil diameter and light and darkness reflexes), alertness and non-pupillary autonomic functions (blood pressure, heart rate, core temperature and salivary output) were measured. Data were analysed by ANOVA, with multiple comparisons. RESULTS: Tropicamide increased resting pupil diameter, velocity and amplitude of the darkness reflex response, and decreased recovery time of the light reflex response. Clonidine affected all these pupillary measures in the opposite direction with the exception of the recovery time. The mydriatic response to tropicamide was potentiated by pre-treatment with clonidine. Clonidine reduced critical flicker fusion frequency, subjective alertness, blood pressure, salivation and temperature. CONCLUSIONS: The potentiation of tropicamide-evoked pupil dilatation by clonidine may be due to the abolition of the increase in parasympathetically mediated pupil constriction due to reduced LC activity.

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers.

RATIONALE: Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be "switched off" by the alpha2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects. OBJECTIVE: The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers. METHODS: Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary "fatigue waves" (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons. RESULTS: Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions. CONCLUSIONS: Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.