Sleep-related memory consolidation in the psychosis spectrum phenotype.

Sleep and memory processing impairments range from mild to severe in the psychosis spectrum. Relationships between memory processing and sleep characteristics have been described for schizophrenia, including unaffected first-degree relatives, but they are less clear across other high-risk groups within the psychosis spectrum. In this study, we investigated high-risk individuals with accumulated risk-factors for psychosis and subthreshold symptoms. Out of 1898 screened individuals, 44 age- and sex-matched participants were sub-grouped into those with substantial environmental risk factors for psychosis and subthreshold psychotic symptoms (high-risk group) and those without these phenotypes (low-risk controls). Four groups (high/low risk, morning/evening training) were trained and tested in the laboratory for sustained attention, motor skill memory (finger-tapping task) and declarative memory (word-pair learning task) immediately after training, again after a night of EEG-recorded sleep at home or a period of daytime wakefulness, and again after 24 h from training. No differences in sustained attention or in memory consolidation of declarative and motor skill memory were found between groups for any time period tested. However, a group difference was found for rapid-eye movement (REM) sleep in relation to motor skill memory: the longer the total sleep time, particularly longer REM sleep, the greater the performance gain, which occurred only in high-risk individuals. In conclusion, our results suggest a gain in motor skill performance with sufficient sleep opportunity for longer REM sleep in high-risk individuals with subthreshold psychotic symptoms. Declarative memory did not benefit from sleep consolidation above or beyond that of the control group.

Hereditary angioedema with a mutation in the plasminogen gene.

BACKGROUND: Hereditary angioedema (HAE) with normal C1-INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or functional mutations in other genes that are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1-INH and without mutation in the F12 gene. METHODS: The study comprised analysis of whole-exome sequencing, Sanger sequencing, and clinical data of patients. RESULTS: We detected a mutation in the plasminogen (PLG) gene in patients with HAEnCI. The mutation c.988A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein. The mutation was identified by next-generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The PLG gene mutation was present in all studied symptomatic patients and was also found in 9 of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). A total of 331 of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes, and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling. CONCLUSIONS: Hereditary angioedema with a mutation in the PLG gene is a novel type of HAE. It is associated with a high risk of tongue swellings.

Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII).

Hereditary angioedema with normal C1 esterase inhibitor and mutations in the F12 gene (HAE-FXII) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. It occurs nearly exclusively in women. We report our experience treating HAE-FXII with discontinuation of potential trigger factors and drug therapies. The study included 72 patients with HAE-FXII. Potential triggers included estrogen-containing oral contraceptives (eOC), hormonal replacement therapy, or angiotensin-converting enzyme inhibitors. Drug treatment comprised plasma-derived C1 inhibitor (pdC1-INH) for acute swelling attacks and progestins, tranexamic acid, and danazol for the prevention of attacks. Discontinuation of eOC was effective in 25 (89.3%) of 28 women and led to a reduction in the number of attacks (about 90%). After ending hormonal replacement therapy, three of eight women became symptom-free. Three women with exacerbation of HAE-FXII during intake of quinapril or enalapril had no further HAE-FXII attacks after discontinuation of those drugs. Eleven women were treated with pdC1-INH for 143 facial attacks. The duration of the treated facial attacks (mean: 26.6 h; SD: 10.1 h) was significantly shorter than that of the previous 88 untreated facial attacks in the same women (mean: 64.1 h; SD: 28.0 h; P < 0.01). The mean reduction in attack frequency was 99.8% under progestins after discontinuing eOC (16 women), 93.8% under tranexamic acid (four women), and 100% under danazol (three women). For patients with HAE-FXII, various treatment options are available which completely or at least partially reduce the number or duration of attacks.

Sleep disturbance in patients taking opioid medication for chronic back pain.

Poor sleep is an increasingly recognised problem with chronic pain and further increases the effect on daily function. To identify the relationship between chronic pain, opioid analgesia and sleep quality, this study investigated activity and sleep patterns in patients taking opioid and non-opioid analgesia for chronic back pain. Thirty-one participants (10 healthy controls, 21 patients with chronic pain: 6 on non-opioid medication; 15 on opioid medication) were assessed using actigraphy, polysomnography and questionnaires. Patients with chronic pain subjectively reported significant sleep and wake disturbances as shown by decreased overall sleep quality (Pittsburgh Sleep Quality Index, p < 0.001), increased symptoms of insomnia (Insomnia Severity Index, p < 0.001) and increased fatigue (Fatigue Severity Scale, p = 0.002). They also spent increased time in bed (p = 0.016), took longer to get to sleep (p = 0.005) and had high interindividual variability in other measures of activity but no overall irregular rest-activity pattern. Patients on high doses of opioids (> 100 mg morphine-equivalent/day) demonstrated distinctly abnormal brain activity during sleep suggesting that polysomnography is necessary to detect sleep disturbance in this population in the absence of irregular rest-activity behaviour. Night-time sleep disturbance is common in individuals suffering from chronic pain and may be further exacerbated by opioid treatment. Considerations must be made regarding the appropriate use of combined actigraphy and miniaturised polysomnography for future population-based studies.

Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations.

BACKGROUND: Hereditary angioedema with normal C1-INH may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or mutations in genes that are still unknown (HAE-unknown). To assess the differences in transmission and inheritance, clinical features, and laboratory parameters between patients with HAE-FXII and HAE-unknown. METHODS: Sixty-nine patients with HAE-FXII from 23 unrelated families and 196 patients with HAE-unknown from 65 unrelated families were studied. RESULTS: Both HAE-FXII and HAE-unknown are inherited as autosomal-dominant traits with incomplete penetrance. The male to female ratio was 1 : 68 in HAE-FXII and 1 : 6.3 in HAE-unknown. The maternal to paternal transmission ratio was 35 : 14 for HAE-FXII and 109 : 12 for HAE-unknown. Mean age at onset of clinical symptoms was 20.3 years in patients with HAE-FXII and 29.6 years in patients with HAE-unknown. The incidence of asphyxiation due to angioedema was similar for HAE-FXII and HAE-unknown. Oral contraceptives and pregnancies had a significantly higher impact on HAE-FXII than on HAE-unknown. Slightly decreased C1-INH activity and C4 concentration were observed in more patients with HAE-FXII than HAE-unknown. Tests for FXI and FXII activity, plasminogen activator inhibitor 1, and activated partial thromboplastin time showed variability but no significant differences between the groups. No abnormalities were found for C1-INH protein, C1q, alpha2-macroglobulin, antithrombin III, and angiotensin-converting enzyme. In families with HAE-FXII, the number of female offspring with F12 mutations was significantly increased and that of male offspring was significantly decreased. CONCLUSIONS: HAE-FXII and HAE-unknown differ in various respects, including gender distribution, genetics, symptoms, and estrogen impact.

Factor X deficiency and intracranial bleeding: who is at risk?

Very few mutations of the gene encoding for coagulation factor X (FX) have been found associated with intracranial haemorrhage (ICH) due to FX deficiency (FXD). No guidelines exist as to when prophylaxis in FXD should be started and how patients at risk for ICH can be identified. We report on a novel mutation causative for ICH in a family of Iranian origin and provide a summary of all published mutations in the FX gene related to ICH. The index patient is an infant with umbilical bleeding requiring blood transfusion in the postnatal period. The international normalized ratio (6.01) and activated partial thromboplastin time (117 s) were prolonged. Coagulation factor analysis was normal except for FX activity (<1%). At 4 months, the child suffered a spontaneous severe intracranial haemorrhage. The child was the product of a consanguineous union. Four of five available family members from three generations displayed minor bleeding symptoms and mildly reduced FX. Sequencing of FX gene demonstrated homozygosity for a novel duplication A (c.1402_1403dupA)* in exon 8 and heterozygosity in four family members. We compare this case to all 15 patients with FXD and ICH and their 11 known mutations described so far. This case illustrates a pattern of FXD (a male neonate with umbilical or gastrointestinal bleeding, very low FX:C (<1%) and an underlying homozygous genotype) who may be at high risk for ICH. In these cases, we recommend to start early prophylactic substitution of FX to prevent a possible life-threatening haemorrhage.

Molecular analysis of FVIII gene in severe HA patients of Costa Rica.

UNLABELLED: Haemophilia A (HA) is X-chromosome linked bleeding disorders caused by deficiency of the coagulation factor VIII (FVIII). It is caused by FVIII gene intron 22 inversion (Inv22) in approximately 45% and by intron 1 inversion (Inv1) in 5% of the patients. Both inversions occur as a result of intrachromosomal recombination between homologous regions, in intron 1 or 22 and their extragenic copy located telomeric to the FVIII gene. The aim of this study was to analyze the presence of these mutations in 25 HA Costa Rican families. PATIENTS, METHODS: We studied 34 HA patients and 110 unrelated obligate members and possible carriers for the presence of Inv22or Inv1. Standard analyses of the factor VIII gene were used incl. Southern blot and long-range polymerase chain reaction for inversion analysis. RESULTS: We found altered Inv22 restriction profiles in 21 patients and 37 carriers. It was found type 1 and type 2 of the inversion of Inv22. During the screening for Inv1 among the HA patient, who were Inv22 negative, we did not found this mutation. DISCUSSION: Our data highlight the importance of the analysis of Inv22 for their association with development of inhibitors in the HA patients and we are continuous searching of Inv1 mutation. This knowledge represents a step for genetic counseling and prevention of the inhibitor development.

Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene.

The congenital FVII deficiency (FVIID) is a rare haemorrhagic disorder with an autosomal recessive pattern of inheritance. Data on phenotype and the genotype from 717 subjects in Central Europe (six countries), Latin America (Costa Rica, Venezuela) and United States, enrolled in the Greifswald Registry of FVII Deficiency were analysed. We detected 131 different mutations in 73 homozygous, 145 compound heterozygous and 499 heterozygous subjects. Regional differences were observed in the mutation pattern and the clinical profile of the evaluated patients. Seventy-one per cent of homozygous and 50% of compound heterozygous subjects were symptomatic. The clinical manifestations of the homozygous subjects were characterized by intracranial haemorrhage (2%), gastrointestinal bleeding (17%), haemarthrosis (13%), epistaxis (58%), gum bleeding (38%), easy bruising (37%), haematoma (15%), haematuria (10%) and menorrhagia (19 of 26 females, 73%). The clinical variability and genotype-phenotype correlation was evaluated in the homozygous subjects. The pattern of bleeding symptoms among compound heterozygous patients was severe and similar to that of the homozygous patients. The large-scale analysis of 499 heterozygous subjects shows that 93 (19%) presented with spontaneous bleeding symptoms such as haemarthrosis (4%), epistaxis (54%), gum bleeding (14%), easy bruising (38%), haematoma (23%), haematuria (5%) and menorrhagia (19 of 45 females; 42%). The severe haemorrhages - intracranial and gastrointestinal - were not reported in heterozygous subjects. The clinical variability and the regional differences in the mutation pattern are discussed regarding care and treatment.

Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene.

Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder. The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known. To understand the association between clinical manifestations and causative genotype, detailed evaluation of bleeding pattern in a high number of patients is needed. This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing. Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized. Twenty-nine different causative mutations, including 15 novel mutations, were analysed. Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%). The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described. The bleeding patterns of the enrolled patients showed differences that are associated with the types of F10 mutation, and the corresponding genotypes. The homozygous patients were evaluated for genotype-phenotype correlation. The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT. A tentative association of other mutations to severe symptoms such as haemarthrosis and GI haemorrhage is reported. The severity of FXD, the genotype-phenotype association, and the results of regional studies are discussed.

Long-term FVII substitution in a preterm infant with severe gastrointestinal bleeding and FVII deficiency due to a homozygous donor splice mutation IVS4+1G-->A.

Congenital FVII deficiency is a rare bleeding disorder. Clinical complications are similar to those seen in hemophilia A, and an increased incidence of intracerebral hemorrhage related to birth trauma has been reported. The authors report on an infant who presented at the second day of life with melaena and hematemesis caused by congenital FVII deficiency with minimal activity of 4%. A homozygous mutation IVS4+G-->A, formerly described in 2 siblings, who died of brain hemorrhage within the first month of life, was identified. Severe bleeding events were prevented with prophylactic treatment. Early identification of the underlying mutation helps to assess the risk of hemorrhage and prevent severe bleeding by prophylactic FVII therapy.

[Factors VII, VIII, IX, and X: molecular genetics and gene diagnosis]. / Gerinnungsfactoren VII, VIII, IX und X. Ausgewählte Aspekte zur Molekulargenetik und Gendiagnostik.

Molecular genetic aspects of the inherited bleeding disorders haemophilia A and B, deficiencies of factor VII and X are described. The spectrum of the mutations is characterized. For genetic counselling the X-chromosomal inheritance of haemophilia and the principles of the indirect and direct genomic diagnosis are explained. Clinics and genetics of the rare inherited bleeding disorders known as factor VII and factor X deficiency are summarized. The mutations spectrum, the role of polymorphisms, the bleeding pattern and genotype-phenotype relations are described.

Thrombosis in inherited factor VII deficiency.

Thrombosis in congenital factor (F) VII deficiency was investigated through extensive phenotypic and molecular-genetic studies. Patients with a history of thrombosis among 514 entries in the FVII Deficiency Study Group database were evaluated. Thrombotic events were arterial in one case, disseminated intravascular coagulation in another and venous in seven. Gene mutations were characterized in eight patients: three were homozygous, three compound heterozygous and two heterozygous. FXa and IIa generation assays were consistent with the genetic lesions. One patient was heterozygous for the FV Leiden and one for the FIIG20210A mutation. In seven patients, surgical interventions and/or replacement therapies had a close temporal relationship with thrombosis, while in the remaining, events were apparently spontaneous. Thromboses were not associated with any specific age, phenotype, mutation zygosity or thrombophilic abnormalities. In particular, severe FVII deficiency did not seem to offer protection from strong thrombosis risk factors such as surgery and replacement therapy.

Treatment of chronic haemophilic synovitis in humans with D-penicillamine.

Chronic proliferative synovitis secondary to haemathroses is a major complication in patients with severe haemophilia. Current management strategies include prophylactic infusions of the missing coagulation factor, corticosteroids, synoviorthesis and/or synovectomy with variable degrees of benefit. In addition, patients with coagulation factor inhibitors are not amenable to the invasive therapeutic modalities. The gross and microscopic findings of the synovitis in haemophilic arthritis are remarkably similar to those seen in patients with rheumatoid arthritis, although the pathophysiology of these two conditions are quite different. Haemophilic arthropathy, in the later stages, resembles degenerative rather than inflammatory joint disease. Oral D-penicillamine, a drug effective in the proliferative synovitis of rheumatoid arthritis, was evaluated in 16 patients. Ten patients had an unequivocal response, while three had a reduction in palpable synovium and three had no response. Thus 81% of the patients had a beneficial response. Minor reversible drug side-effects occurred in two patients (proteinuria in one and a rash in the second). The results of this study suggest that D-penicillamine is an effective and safe drug for the treatment of haemophilic chronic synovitis.

[Emergence of circadian rhythms in infants before and after birth: evidence for variations by parental influence]. / Der Einfluss der elterlichen Tagesrhythmik vor und nach der Geburt auf die Entwicklung der Tagesrhythmik beim Säugling.

BACKGROUND: Organisms have developed endogenous mechanisms for keeping track of time which allow them to adjust to environmental changes. Entrainment of endogenous rhythms to the day-night cycle is of elementary importance for the regulation of physiological processes. How environmental changes influence the manifestation of circadian rhythms during intrauterine and extrauterine growth depend on complex networking of molecular, physiological and sensory mechanisms. This work reports on development of circadian rhythms in the infant, with particular emphasis on the roles of times cues to which the infant is exposed. SUBJECTS AND METHODS: Activity data of 12 families were continuously recorded during the first 4 months after birth using non-invasive actigraphs. Recordings of parental activity started at the 3rd trimester of pregnancy. Time series analysis was used to investigate the periodic structure of the data. In addition, we review the literature on the ontogenesis of circadian rhythms in humans. RESULTS: During the 3rd trimester, daily variation of physiological functions in the fetus showed a high degree of correspondence with maternal circadian rhythms. Early behaviour of most infants was highly variable between individuals but could be assigned to different entrainment patterns. Good correspondence of mother-infant activity patterns during the early postnatal period, when the infant was not yet entrained to the day-night-cycle, was correlated with the rapid development of an entrained daily pattern in the infant a few weeks later. CONCLUSION: Understanding the emergence of periodic structures at physiological and behavioural level during human ontogenesis will be an asset in the successful intervention and treatment during neonatal care.

Expression of N-acetyltransferases in periodontal granulation tissue.

Smoking is a major risk of periodontal diseases. At the site of first contact, the gingiva is exposed to aromatic amines and polycyclic hydrocarbons. These are metabolized by the N-acetyltransferases (NAT), leading to local detoxification and/or activation reactions contributing to the risk of periodontal destruction in smokers. The purpose of this study was to detect the expression of N-acetyltransferase isoenzymes NAT1 and NAT2 in periodontal granulation tissue. In 24 specimens obtained from periodontitis patients or control subjects, mRNA encoding for NAT1 and NAT2 was detected by RT-PCR, and proteins were identified by immunohistochemistry. In periodontal granulation tissues, immunoreactivity for NAT1 and NAT2 was detected in infiltrating leukocytes and fibroblasts. In normal gingiva, both enzymes were found in epithelial cells, whereas NAT1 was also detected in endothelial cells. The results suggest that these enzymes may play a role in the defense against xenobiotics and the accelerated progression of periodontal disease in smokers.

Ultradian and circadian activity-rest rhythms of preterm neonates compared to full-term neonates using actigraphic monitoring.

During the first weeks of life, preterm neonates show fewer circadian rhythms in their physiological parameters than full-term neonates. To determine whether preterm neonates differ in their temporal adaptation to the day-night cycle from full-term neonates at the early age of 1 week, we compared activity-rest behavior of both groups. Activity-rest behavior of 10 neurologically healthy preterm neonates (born in 34th to 36th week of gestation) and 10 neurologically healthy full-term neonates (born in 37th to 42nd week of gestation) was monitored longitudinally for 8 successive days in the first 2 weeks of life. Actigraphy was used to register and display time patterns of activity and rest in neonates by using small actometers, which resemble a wristwatch. Nursing/feeding was recorded using the actometer's integrated event marker button. Recordings for preterm neonates were conducted in the hospital, recordings for full-term neonates were carried out in the hospital and in their homes. In addition to the actigraphic recordings, a standardized diary was kept regularly. To assess periodic characteristics, frequency components of activity-rest behavior were analyzed using fast Fourier transformation (FFT). Amounts of daily sleep time, nightly sleep time, and sleep time during 24h were compared. Nursing/feeding epochs were also analyzed for 5 preterm and 5 full-term neonates to compare their food intake behavior. The majority of preterm neonates showed a multitude of ultradian frequencies in their spectra. In contrast, several full-term neonates showed a distinct circadian frequency. In preterm neonates, average nightly sleep and average daily sleep of all recorded days were very similar, but after the fourth day of life, only average nightly sleep increased. In full-term neonates, average nightly and daily sleep time of all recorded days differed by about 1h. Average sleep time during 24h for preterm and full-term neonates was similar. Preterm neonates showed longer intervals between events of food intake than full-term neonates. The circadian peaks in the frequency spectra of full-term neonates may indicate the initial adaptation in the first week of life to a 24h day. This is in agreement with our results concerning the different durations of nightly and daily sleep. The increase in nightly sleep time of preterm neonates may be attributed to the progressing adaptation to a circadian activity-rest pattern.

Lithuanian haemophilia A and B registry comprising phenotypic and genotypic data.

Haemophilia represents the most common hereditary severe bleeding disorder in humans. About 100 families with this condition live in Lithuania, one of the Baltic states with a population of 3.7 million. Haemophilia care and genetic counselling are still rendered difficult owing to limited availability of clotting factor concentrate and molecular genetic diagnosis. In the present study, a haemophilia registry, comprising phenotypic and genotypic data of the majority of Lithuanian haemophilia A and B patients, was established. The phenotype includes the degree of severity, factor VIII:C, factor VIII:Ag, factor IX:C, von Willebrand factor and antigen (VWF:RiCoF, vWF:Ag) and inhibitor status. Genotyping of the factor VIII and IX genes was performed using mutation screening methods and direct sequencing. In 61 out of 63 patients with haemophilia A (96.8%) and all eight patients with haemophilia B (100%), the causative mutations could be detected. Nineteen of the factor VIII gene defects and two of the factor IX gene mutations are reported for the first time. Identified mutations allowed direct carrier diagnosis in 83 female relatives revealing 44 carriers, 38 non-carriers and one somatic mosaicism. The information provided by this registry will be helpful for monitoring the treatment of Lithuanian haemophilia patients and also for reliable genetic counselling of the affected families in the future.