Heparin-induced thrombocytopenia: pathophysiology and new treatment options

Heparin induced thrombocytopenia (HIT) is a severe complication of heparin therapy. It is generally accompanied by a paradoxical decrease in platelets leading to activation of platelets and of the coagulation system. HIT type I is a mild, transient, non-immune disorder. HIT type II is an immune-mediated reaction towards neo-antigen on PF4, which is platelet factor 4 (PF4) that is exposed upon binding to heparins. A low sulfated octasaccharide is required for binding to PF4. The generated immunoglobulines bridge platelets by binding to the FcgRIIa-receptor. In patients with HIT type II heparin/LMW-heparin has to be discontinued immediately upon clinical suspicion. Diagnosis can be confirmed by laboratory tests. As patients are at high risk for or because they have developed thromboembolism, anticoagulation is mandatory, despite thrombocytopenia. Treatment options are danaparoid, r-hirudin, bivalirudin, argatroban, dextransulfate, and dermatansulfate. In future, fondaparinux and ximelagatran may be considered for treatment.     

Delayed sleep phase syndrome is related to seasonal affective disorder

Background

Both delayed sleep phase syndrome (DSPS) and seasonal affective disorder (SAD) may manifest similar delayed circadian phase problems. However, the relationships and co-morbidity between the two conditions have not been fully studied. The authors examined the comorbidity between DSPS and SAD.

Methods

We recruited a case series of 327 DSPS and 331 controls with normal sleep, roughly matched for age, gender, and ancestry. Both DSPS and controls completed extensive questionnaires about sleep, the morningness-eveningness trait, depression, mania, seasonality of symptoms, etc.

Results

The prevalences of SAD and subsyndromal SAD (S-SAD) were higher in DSPS compared to controls (χ² = 12.65, p = 0.002). DSPS were 3.3 times more likely to report SAD (odds ratio, 3.34; 95% CI, 1.41-7.93) compared to controls as defined by the Seasonal Pattern Assessment Questionnaire (SPAQ). Correspondingly, DSPS showed significantly higher seasonality scores compared to controls in mood, appetite, and energy level subscores and the global seasonality score (t = 3.12, t = 0.002; t = 2.04, p = 0.041; t = 2.64, p = 0.008; and t = 2.15, p = 0.032, respectively). Weight fluctuation during seasons and winter-summer sleep length differences were also significantly higher in DSPS than controls (t = 5.16, p < 0.001 and t = 2.64, p = 0.009, respectively). SAD and S-SAD reported significantly higher eveningness, higher depression self-ratings, and more previous mania symptoms compared to non-seasonal subjects regardless of whether they were DSPS or controls.

Conclusions

These cases suggested that DSPS is partially comorbid with SAD. These data support the hypothesis that DSPS and SAD may share a pathophysiological mechanism causing delayed circadian phase.     

Delayed sleep phase disorder in temporal isolation

STUDY OBJECTIVES: This study sought to characterize sleep and the circadian rhythm of body core temperature of an individual with delayed sleep phase disorder (DSPD) in the absence of temporal cues and social entrainment and to compare those measures to age-matched normal control subjects studied under identical conditions. DESIGN: Polysomnography and body temperature were recorded continuously for 4 days in entrained conditions, followed immediately by 17 days in a "free-running" environment. SETTING: Temporal isolation facility in the Laboratory of Human Chronobiology, Weill Cornell Medical College. PARTICIPANTS: One individual who met criteria for delayed sleep phase disorder according to the International Classification of Sleep Disorders Diagnostic and Coding Manual (ICSD-2) and 3 age-matched control subjects. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The DSPD subject had a spontaneous period length (tau) of 25.38 hours compared to an average tau of 24.44 hours for the healthy controls. The DSPD subject also showed an altered phase relationship between sleep/wake and body temperature rhythms, as well as longer sleep latency, poorer sleep efficiency, and altered distribution of slow wave sleep (SWS) within sleep episodes, compared to control subjects. CONCLUSIONS: Delayed sleep phase disorder may be the reflection of an abnormal circadian timing system characterized not only by a long tau, but also by an altered internal phase relationship between the sleep/wake system and the circadian rhythm of body temperature. The latter results in significantly disturbed sleep, even when DSPD patients are permitted to sleep and wake at their preferred times.     

Phase-dependent treatment of delayed sleep phase syndrome with melatonin

STUDY OBJECTIVE: Delayed sleep phase syndrome (DSPS) is a circadian-rhythm sleep disorder characterized by abnormally late sleep and wake times. Melatonin, taken in the evening, advances sleep and circadian phase in patients with DSPS. However, little is known about the most effective dose or time of administration. In the present study, we tested the effectiveness of melatonin to advance the timing of sleep and circadian phase in individuals with DSPS. DESIGN: Following baseline assessment of sleep and circadian phase, subjects were randomly assigned to 1 of 3 treatment groups. The administration of melatonin (0.3 or 3.0 mg) or placebo was double-blinded. SETTING: All procedures were conducted on an outpatient basis. PARTICIPANTS: Thirteen subjects with DSPS, recruited via flyers, advertisements, and referrals from the Sleep Clinic, completed this study. INTERVENTIONS: Melatonin (0.3 or 3.0 mg) or placebo was administered between 1.5 and 6.5 hours prior to dim light melatonin onset for a 4-week period. MEASUREMENTS AND RESULTS: Both doses of melatonin advanced the circadian phase of endogenous melatonin. The magnitude of phase advance in dim-light melatonin onset correlated strongly with the time of melatonin administration, with earlier times being more effective (r2 = 0.94, P < .0001). Similar, though weaker, relationships were obtained between the timing of melatonin administration and changes in sleep time. CONCLUSIONS: These results indicate that melatonin advances the circadian clock and sleep in patients with DSPS in a phase-dependent manner. This is the first study that reports a relationship between timing of melatonin administration and phase changes in patients with DSPS.     

Cyclic vomiting syndrome: treatment options

Cyclic vomiting syndrome is a disorder characterized by recurrent episodes of severe nausea and vomiting separated by symptom-free periods. Our aims were to review treatments of adult cyclic vomiting syndrome as well as to identify areas for further clinical research and the unanswered questions in this field. We conducted a PubMed search using such keywords as “cyclic vomiting syndrome,” “nausea,” “vomiting,” “treatment,” “trigger factors” and “tricyclic antidepressants” and combined this information with the knowledge and clinical research from the authors. Available data show that in adult cyclic vomiting syndrome, there is an impressive and sustained response to high-dose tricyclic antidepressants. In up to 13 % who are regarded as poor responders to tricyclic antidepressants, a predictable profile can be identified related to coexisting psychological disorders, marijuana use, poorly controlled migraine headache or chronic narcotic use. Cyclic vomiting syndrome in adults is being an increasingly recognized entity. Tricyclic antidepressants are the main treatment for controlling symptoms. Eliminating and addressing trigger factors are an essential part of management.     

Phase-shifting effects of bright morning light as treatment for delayed sleep phase syndrome

Bright light has recently been shown to have phase-shifting effects on human circadian rhythms. In this study we applied this effect to 20 patients with delayed sleep phase syndrome (DSPS) who were unable to fall asleep at conventional clock times and had a problem staying alert in the morning. In a controlled treatment study, we found that 2 h of bright light exposure in the morning together with light restriction in the evening successfully phase advanced circadian rhythms of core body temperature and multiple sleep latencies in these patients. This finding corroborates the importance of light for entraining human circadian rhythms.     

Circadian phase in delayed sleep phase syndrome: predictors and temporal stability across multiple assessments

STUDY OBJECTIVES: To assess temporal stability across multiple assessments and predictors of circadian phase in participants with delayed sleep phase syndrome (DSPS), relative to normal-sleeping matched controls. DESIGN: Circadian phase was assessed by salivary dim light melatonin onset (DLMO) during 3 laboratory visits, separated by at least 5 days--2 scheduled at the end of the week (Friday) and 1 scheduled at the end of the weekend (Sunday). PATIENTS: Eight young volunteers who met International Classification of Sleep Disorders-Revised criteria for DSPS, and 8 age- and sex-matched controls (age range 19-27 years old). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: As expected, salivary DLMO occurred significantly later in patients with DSPS than in controls (F 10.561, p = .006). However, circadian phase did not change significantly across the 3 DLMO assessments in either group. Estimations of circadian phase were not significantly different in the assessments conducted on weekdays versus weekends. Predictors of circadian phase included time of morning light exposure (R2 = 0.777; p < .001), recent wake time (R2 = 0.701, p < .001), and self-reported chronotype (R2 = 0.320, p = .016). DLMO preceded wake time in both groups by approximately 10.75 hours. CONCLUSIONS: Across serial laboratory assessments on an ad lib sleep schedule, patients with DSPS appeared more similar to than different from normal-sleeping control subjects, except for a stable delay in circadian phase.     

Repetitive behaviors in CHARGE syndrome: differential diagnosis and treatment options

Twenty-nine students with CHARGE syndrome were evaluated using the Compulsive Behavior Checklist (CBC). Most of the students obtained a high score for repetitive behaviors, averaging 11.5 repetitive behaviors per student. Most students' repetitive behaviors significantly interfered with their daily routine. Thirty-four percent of the students responded to redirection with aggression toward themselves or others. Many of these behaviors do not respond well to traditional behavioral techniques. Through observation, definitions, and using functional analysis of behavior, repetitive behaviors were assigned to one of four categories. Each category has different treatment options. A case study of an adolescent girl with CHARGE syndrome who has profound deafness, colobomas, and moderate cognitive delay is presented. She displayed severe behavior challenges and significant medical issues. The course of treatment is outlined over 5 years. Behavior management, medical management, and psychiatric management were used in regulating her behavior, medical issues, and anxiety disorder. Close coordination between disciplines and excellent family involvement led to a very positive outcome. The student, now 19 years old, has made progress in her educational program and has been able to experience more community integration.     

Prevalence, pathophysiology, health consequences and treatment options of obesity in the elderly: a guideline

The prevalence of obesity is rising progressively, even among older age groups. By the year 2030-2035 over 20% of the adult US population and over 25% of the Europeans will be aged 65 years and older. The predicted prevalence of obesity in Americans, 60 years and older was 37% in 2010. The predicted prevalence of obesity in Europe in 2015 varies between 20 and 30% dependent on the model used. This means 20.9 million obese 60+ people in the USA in 2010 and 32 million obese elders in 2015 in the EU. Although cut-off values of BMI, waist circumference and percentages of fat mass have not been defined for the elderly (nor for the elderly of different ethnicity), it is clear from several meta-analyses that mortality and morbidity associated with overweight and obesity only increases at a BMI above 30 kg/m(2). Thus, treatment should only be offered to patients who are obese rather than overweight and who also have functional impairments, metabolic complications or obesity-related diseases, that can benefit from weight loss. The weight loss therapy should aim to minimize muscle and bone loss but also vigilance as regards the development of sarcopenic obesity - a combination of an unhealthy excess of body fat with a detrimental loss of muscle and fat-free mass including bone - is important in the elderly, who are vulnerable to this outcome. Life-style intervention should be the first step and consists of a diet with a 500 kcal (2.1 MJ) energy deficit and an adequate intake of protein of high biological quality together with calcium and vitamin D, behavioural therapy and multi-component exercise. Multi-component exercise includes flexibility training, balance training, aerobic exercise and resistance training. The adherence rate in most studies is around 75%. Knowledge of constraints and modulators of physical inactivity should be of help to engage the elderly in physical activity. The role of pharmacotherapy and bariatric surgery in the elderly is largely unknown as in most studies people aged 65 years and older have been excluded.     

Delayed sleep phase syndrome: A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset

In a double-blind placebo-controlled cross-over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double-blind setting and two weeks in an open setting successively or interrupted by two weeks of placebo. The study's impact was assessed by measurements of the 24-h curves of endogenous melatonin production and rectal temperature (n=14), polysomnography (n=22), actigraphy (n=13), sleep log (n=22), and subjective sleep quality (n=25). Mean dim light melatonin onset (DLMO) (±SD), before treatment, occurred at 23.17 hours (±138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.     

Arousals and sleep stages in patients with obstructive sleep apnoea syndrome: changes under nCPAP treatment

Nocturnal arousals are the essential cause of disturbed sleep structure in patients with obstructive sleep apnoea syndrome (OSAS). The aim of this study was to analyse the relationship between sleep stages, respiratory (type-R) and movement (type-M) related EEG arousals. Furthermore, the value of these arousals as a criterion for the efficiency of nCPAP treatment was estimated. We examined 38 male patients aged between 30 and 71 (49.1±20.9 SD) y. All patients suffered from OSAS. The mean respiratory disturbance index (RDI) was 47.3±27.8 per h. Polysomnographic monitoring was carried out on 4 subsequent nights: baseline night, 2 nights of nCPAP titration and nCPAP control night. Sleep was visually scored and EEG arousals were classified into type R and M, depending on whether changes of respiration or movement caused the arousal. The RDI, the R index (type-R/h), the M index (type-M/h) and the R and M indices in different sleep stages were calculated. During the baseline night a deficit of slow wave sleep (SWS) and REM sleep was found. Furthermore there were more type-R than type-M arousals registered (17.4 h^?1[3.6–43.6] vs. 5.9 h^?1[1.6–11.8]) ( P <0.01). They occurred during stages NREM 1, NREM 2 and REM ( P <0.01). An SWS sleep rebound and a reduction of the SWS and REM latencies were already found during the first CPAP night. The R index was reduced during the first CPAP night in all sleep stages ( P <0.01) and remained approximately the same in the following 2 nights (3. CPAP night: 1.1 h^?1[0.3–5.0]). Type M arousals occurred more in stages 1 and 2 ( P <0.01), and remained unchanged under nCPAP. We concluded that differentiation of nocturnal arousals may provide more detailed information regarding the influence of breathing disturbances on sleep. Respiratory related, not movement related, arousals may be a useful additional tool in judging the efficiency of OSAS.     

Metabolic syndrome: pathophysiology and impact on lithogenesis

In our societies, the increase of the frequency of the diseases of overweight, in particular obesity, diabetes type 2 and metabolic syndrome, coincides with that of the urinary lithiasis. Like the lithiasic disease, the metabolic syndrome or syndrome X is multi-factor. Several epidemiological studies were interested in research of a physiopathological relation between the various components of this syndrome (obesity, arterial hypertension, diabetes, dyslipemy) and lithogenesis. During the metabolic syndrome, resistance to insulin and the defect of renal ammoniogenesis constitute the principal disorders supporting lithogenesis. The defect of renal ammoniogenesis armature by the resistance of the renal cells to insulin involves a urinary hyperacidity which supports the crystallization of the uric acid responsible for the formation of uric or mixed uric acid/oxalate stones.     

A common pathophysiology for sudden cot death and sleep apnoea. "The vacuum-glossoptosis syndrome".

Several congenital and acquired conditions, characterized by upper airway narrowing, may result in respiratory, cardiac, and sleep disturbances. In all these conditions the leading clinical feature is the occurrence of cyclic obstructive apnoea, mainly during sleep. The common pathogenic mechanism for the airway occlusion seems to be a backward displacement of the tongue and mandible, favoured by the muscle relaxation which occurs during sleep and by gravity in the supine position. A constant factor determining the glossoptosis is the pharyngeal vacuum occurring in these conditions as a result of inspiratory efforts in face of a narrowed upper airway. The response to this type of obstruction is age-dependent, since only in early infancy may these apnoeic spells be life-threatening. A similar pathophysiology is suggested for sudden cot death, which could be considered as a peculiar presentation of this "vacuum-glossoptosis syndrome". This hypothesis could explain why sudden cot death is often associated with nasopharyngitis and occurs always in infancy, almost invariably during sleep.     

Piriformis syndrome: implications of anatomical variations, diagnostic techniques, and treatment options

Details of piriformis syndrome, including the proper diagnosis and most effective form of treatment, continue to be controversial. While the cause, diagnosis, and treatment of piriformis syndrome remain elusive, many studies have been conducted to investigate newly developed diagnostic techniques as well as various treatment options for piriformis-induced sciatica. Despite the quantity of literature, few studies have demonstrated statistically significant results that support one form of treatment over another. Thus, despite the evidence supporting the newer treatment methodologies for piriformis syndrome, research should continue. It is important not only to evaluate treatment outcomes based on associated pain relief, but also to investigate the functional and anatomical return that patients experience from these studied treatments in order to fully explore the most effective form of therapy for piriformis syndrome.     

Efficacy of enhanced evening light for advanced sleep phase syndrome

This study tested whether a newly designed enhanced evening light therapy was well tolerated and effective in relieving symptoms of Advanced Sleep Phase Syndrome (ASPS). Participants with self-reported ASPS symptoms were 47 older adults (21 men and 26 women, age 60-86). After baseline, participants underwent 28 consecutive days of either dim or enhanced intensity light treatment for 2-3 hr in the evening. Enhanced evening light (~265 lux) exposure was no more effective than a placebo dim light (~2 lux) at alleviating advanced sleep phase as measured by actigraphically recorded sleep and urinary 6-sulphatoxymelatonin (aMT6s) excretion patterns. Participants receiving the enhanced light reported subjective benefit and a significant delay in sleep onset as compared to the placebo. Although compliance was good and the new enhanced evening light therapy design was well tolerated, the benefits were statistically equivocal.     

The rumination syndrome in adults: a review of the pathophysiology, diagnosis and treatment

Rumination in adults is considered to be the effortless regurgitation of recently ingested food into the mouth, followed by either rechewing and reswallowing or expulsion of the regurgitate. On the basis of the definition of rumination as a unique category of functional gastroduodenal disorders, according to the newly established Rome III classification, a review of the pathophysiology, diagnosis and treatment of the rumination syndrome in adults is presented after systematic and critical approach of all articles that could be retrieved through PubMed using the term "rumination".     

Two pedigrees of familial advanced sleep phase syndrome in Japan

STUDY OBJECTIVES: To determine whether a known missense mutation (bp2106 A/G) in hPer2 (a human homolog of the Drosophila period gene) for familial advanced sleep phase syndrome in a Caucasian family is involved in Japanese familial advanced sleep phase syndrome pedigrees. MEASUREMENTS AND RESULTS: We identified 2 new Japanese families with advanced sleep phase syndrome, and a systematic survey was carried out in 28 relatives of theses 2 families. A total of 9 affected subjects were identified. The affected members showed significantly strong morningness tendencies compared with the unaffected members in various circadian parameters including the Horne-Ostberg Morningness-Eveningness Questionnaire score (77.3 +/- 4.8 vs 57.5 +/- 7.6, p < 0.001), average sleep-onset time (20:45 +/- 75 min vs 23:16 +/- 64 min, p < 0.02), and average wake time (4:55 +/- 38 min vs 6:13 +/- 25 min, p < 0.01), as well as saliva dim-light melatonin-onset time (20:15 +/- 21 min vs 22:25 +/- 65 min, p < 0.02). DNA samples were obtained from 7 affected and 7 unaffected subjects. None of the tested subjects possessed the missense mutation (bp2106 A/G) in hPer2. Furthermore, there is no significant linkage between affected subjects with hPer2 region by 2-point mapping and by direct sequencing of 23 exons of hPer2. CONCLUSION: These findings support the notion of genetic heterogeneity of familial advanced sleep phase syndrome cases in humans. The search for more familial advanced sleep phase syndrome cases and for loci other than hPer2 are necessary to further examine the roles of circadian-related genes in genetically determined human circadian rhythm disorders.     

Cognitive function and treatment of obstructive sleep apnea syndrome

Among patients with obstructive sleep apnea syndrome (OSAS), impairment of cognitive function, i.e. deficits in memory, attention, and visuconstructive abilities are common. We applied different forms of treatment for patients with newly diagnosed OSAS in a randomized study with a one-year follow-up. Patients with BMI > 40 kg/m2 were excluded. After the initial diagnostic work-up, male patients were considered to be candidates for either nasal continuous airway pressure (nCPAP) (27 patients) or surgical treatment (uvulopalatopharyngoplasty with or without mandibular osteotomy) (23 patients). Within the groups, the patients were then randomized to active treatment (nCPAP/surgery) or to conservative management. Cognitive function and severity of OSAS were assessed prior to treatment and 3 and 12 months later. At 12 months, all patients on nCPAP had a normal ODI4 index (< 10), and were significantly less somnolent than their controls; 3/11 of the surgically treated patients had a normal ODI4 index. Daytime somnolence was significantly less severe in the surgically treated patients than in their controls. Cognitive function did not correlate importantly with daytime sleepiness or severity of OSAS; the best Pearson pairwise correlation coefficient was between ODI4 and the Bourdon-Wiersma (r = 0.36). Success in treatment of OSAS did not affect neuropsychological outcome. We concluded that the standard cognitive test battery is insufficiently sensitive to identify positive changes in patients with OSAS, especially among those with a high level of overall mental functioning.