Lipoprotein(a) levels and carotid intima-media thickness in children: A 20-year follow-up study.

Elevated lipoprotein(a) [Lp(a)] is independently associated with cardiovascular disease (CVD). In a recent long-term follow-up study involving children with familial hypercholesterolemia, Lp(a) levels contributed significantly to early atherosclerosis, as measured by carotid intima-media thickness (cIMT). To determine if this holds true for children without FH, we conducted a 20-year follow-up study, examining 88 unaffected siblings (mean age: 12.9 years) of children with FH. No significant association was found between Lp(a) and cIMT during follow-up (ß-adjusted [95% CI] = 0.0001 [-0.008 to 0.008] mm per 50 nmol/L increase Lp(a), p = 0.97). In conclusion, our findings suggest that elevated levels of Lp(a) do not play a significant role in arterial wall thickening among children without FH during the 20-year follow-up period. This leads us to consider the possibility that cIMT may not be a suitable marker for detecting potential subtle changes in the arterial wall mediated by Lp(a) in the young, general population. However, it could also be that elevated Lp(a) is only a significant risk factor for atherosclerosis in the presence of other risk factors such as FH.

Bacterial reservoir in deeper skin is a potential source for surgical site and biomaterial-associated infections.

BACKGROUND: The origin of surgical site and biomaterial-associated infection is still elusive. Micro-organisms contaminating the wound may come from the air in the operating theatre, the surgical team or the skin of the patient. The skin of patients is disinfected prior to surgery, but bacteria deeper in the skin (e.g. in sweat glands or sebaceous glands) may not be reached. METHODS: A preliminary cohort study was performed to study the origin of surgical site and biomaterial-associated infection between May 2020 and February 2021. In order to investigate whether cutaneous microbiota colonize the wound when released from the skin upon cutting, aerobic and anaerobic bacteria were isolated, quantified and identified from the skin of 99 patients undergoing trauma surgery, before and after skin disinfection, from knife blades and from the wound directly after the first cut. RESULTS: Ninety-nine percent of the patients were culture-positive before disinfection with chlorhexidine. Of these, 40% were still culture-positive after disinfection. Of these, 54% had a positive culture of the wound after cutting the skin. Twenty percent of the patients with a negative culture after disinfection had a positive wound culture after cutting the skin. Staphylococcus epidermidis and Cutibacterium acnes were the most commonly cultured bacterial species. In 9% of cases, more than 100 bacterial colonies were cultured from the wound; this may cause biomaterial-associated infection. CONCLUSION: Bacteria residing in the skin and not eradicated by disinfection may enter the surgical wound upon cutting, resulting in contamination which may cause biomaterial-associated infection.

Closing the loop: Novel quantitative fMRI approach for manipulation of the sensorimotor loop in tremor.

Tremor is thought to be an effect of oscillatory activity within the sensorimotor network. To date, the underlying pathological brain networks are not fully understood. Disentangling tremor activity from voluntary motor output and sensorimotor feedback systems is challenging. To better understand the intrinsic sensorimotor fingerprint underlying tremor, we aimed to disentangle the sensorimotor system into driving (motor) and feedback/compensatory (sensory) neuronal involvement, and aimed to pinpoint tremor activity in essential tremor (ET) and tremor-dominant Parkinson's disease (PD) with a novel closed-loop approach. Eighteen ET patients, 14 tremor-dominant PD patients, and 18 healthy controls were included. An MR-compatible wrist manipulator was employed during functional MRI (fMRI) while muscle activity during (in)voluntary movements was concurrently recorded using electromyography (EMG). Tremor was quantified based on EMG and correlated to brain activity. Participants performed three tasks: an active wrist motor task, a passive wrist movement task, and rest (no wrist movement). The results in healthy controls proved that our experimental paradigm activated the expected motor and sensory networks separately using the active (motor) and passive (sensory) task. ET patients showed similar patterns of activation within the motor and sensory networks. PD patients had less activity during the active motor task in the cerebellum and basal ganglia compared to ET and healthy controls. EMG showed that in ET, tremor fluctuations correlated positively with activity in the inferior olive region, and that in PD tremor fluctuations correlated positively with cerebellar activity. Our novel approach with an MR-compatible wrist manipulator, allowed to investigate the involvement of the motor and sensory networks separately, and as such to better understand tremor pathophysiology. In ET sensorimotor network function did not differ from healthy controls. PD showed less motor-related activity. Focusing on tremor, our results indicate involvement of the inferior olive in ET tremor modulation, and cerebellar involvement in PD tremor modulation.

Two years' experience with inspiration breath-hold in liver SBRT.

•The workflow of inspiration breath-hold SBRT for liver metastases is described.•Inspiration breath-hold in liver SBRT is feasible for 95% of the patients.•An individual margin recipe for inspiration breath-hold liver SBRT is explained.•Margin reduction of 10 mm using inspiration breath-hold compared to free breathing.

A chlorhexidine-releasing epoxy-based coating on titanium implants prevents Staphylococcus aureus experimental biomaterial-associated infection.

Prevention of biomaterial-associated infections (BAI) remains a challenging problem, in particular due to the increased risk of resistance development with the current antibiotic-based strategies. Metallic orthopaedic devices, such as non-cemented implants, are often inserted under high mechanical stress. These non-cemented implants cannot be protected by e.g. antibioticreleasing bone cement or other antimicrobial approaches, such as the use of bioactive glass. Therefore, in order to avoid abrasion during implantation procedures, we developed an antimicrobial coating with great mechanical stability for orthopaedic implants, to prevent Staphylococcus aureus BAI. We incorporated 5 and 10 wt % chlorhexidine in a novel mechanically stable epoxy-based coating, designated CHX5 and CHX10, respectively. The coatings displayed potent bactericidal activity in vitro against S. aureus, with over 80 % of the release (19 µg/cm2 for CHX5 and 41 µg/cm2 for CHX10) occurring within the first 24 h. In mice, the CHX10 coating significantly reduced the number of CFU (colony forming units), both on the implants and in the peri-implant tissues, 1 d after S. aureus challenge. The CHX10-coated implants were well-tolerated by the animals, with no signs of toxicity observed by histological analysis. Moreover, the coating significantly reduced the frequency of culture-positive tissues 1 d, and of culture-positive implants 1 and 4 d after challenge. In summary, the chlorhexidine-releasing mechanically stable epoxy-based CHX10 coating prevented implant colonisation and S. aureus BAI in mice and has good prospects for clinical development.

Fabrication of oxide layer on zirconium by micro-arc oxidation: Structural and antimicrobial characteristics.

The aim of this study was to cover the surfaces of zirconium (Zr) with an antimicrobial layer for biomedical applications. For this purpose, the micro-arc oxidation (MAO) process was employed in a sodium silicate and sodium hydroxide containing base electrolyte with and without addition of silver acetate (AgC2H3O2). In general, synthesized MAO layers were composed of zirconium oxide (ZrO2) and zircon (ZrSiO4). Addition of AgC2H3O2 into the base electrolyte caused homogenous precipitation of silver-containing particles in the MAO layer, which exhibited excellent antibacterial efficiency against methicillin-resistant Staphylococcus aureus (MRSA) as compared to the untreated and MAO-treated Zr.

Prevention of Staphylococcus aureus biomaterial-associated infections using a polymer-lipid coating containing the antimicrobial peptide OP-145.

The scarcity of current antibiotic-based strategies to prevent biomaterial-associated infections (BAI) and their risk of resistance development prompted us to develop a novel antimicrobial implant-coating to prevent Staphylococcus aureus-induced BAI. We incorporated the antimicrobial peptide OP-145 into a Polymer-Lipid Encapsulation MatriX (PLEX)-coating to obtain high peptide levels for prolonged periods at the implant-tissue interphase. We first confirmed that OP-145 was highly effective in killing S. aureus and inhibiting biofilm formation in vitro. OP-145 injected along S. aureus-inoculated implants in mice significantly reduced the number of culture-positive implants. OP-145 was released from the PLEX coating in a controlled zero-order kinetic rate after an initial 55%-burst release and displayed bactericidal activity in vitro. In a rabbit intramedullary nail-related infection model, 67% of rabbits with PLEX-OP-145-coated nails had culture-negative nails after 28days compared to 29% of rabbits with uncoated nails. In rabbits with PLEX-OP-145-coated nails, bone and soft tissue samples were culture-negative in 67% and 80%, respectively, whereas all bone samples and 71% of the soft tissue samples of rabbits with uncoated nails were infected. Together, PLEX-OP-145 coatings, of which both compounds have already been found safe in man, can prevent implant colonization and S. aureus-induced BAIs.

Fat/water ratios measured with diffuse reflectance spectroscopy to detect breast tumor boundaries.

Recognition of the tumor during breast-conserving surgery (BCS) can be very difficult and currently a robust method of margin assessment for the surgical setting is not available. As a result, tumor-positive margins, which require additional treatment, are not found until histopathologic evaluation. With diffuse reflectance spectroscopy (DRS), tissue can be characterized during surgery based on optical parameters that are related to the tissue morphology and composition. Here we investigate which optical parameters are able to detect tumor in an area with a mixture of benign and tumor tissue and hence which parameters are most suitable for intra-operative margin assessment. DRS spectra (400-1600 nm) were obtained from 16 ex vivo lumpectomy specimens from benign, tumor border, and tumor tissue. One mastectomy specimen was used with a custom-made grid for validation purposes. The optical parameter related to the absorption of fat and water (F/W-ratio) in the extended near-infrared wavelength region (~1000-1600 nm) provided the best discrimination between benign and tumor sites resulting in a sensitivity and specificity of 100 % (excluding the border sites). Per patient, the scaled F/W-ratio gradually decreased from grossly benign tissue towards the tumor in 87.5 % of the specimens. In one test case, based on a predefined F/W-ratio for boundary tissue of 0.58, DRS produced a surgical resection plane that nearly overlapped with a 2-mm rim of benign tissue, 2 mm being the most widely accepted definition of a negative margin. The F/W-ratio provided excellent discrimination between sites clearly inside or outside the tumor and was able to detect the border of the tumor in one test case. This work shows the potential for DRS to guide the surgeon during BCS.

Neurodevelopmental retardation, as assessed clinically and with magnetoencephalography and electroencephalography, associated with perinatal dioxin exposure.

UNLABELLED: In 1980s Western Europe, human perinatal exposure to background levels of dioxins was rather high. We therefore evaluated the neurodevelopment of our cohort during the prepubertal period and in adolescence. At prepubertal age (7-12 years) 41 children were tested. Both neuromotor functioning and psychological testing were performed (Dutch version of the Wechsler Intelligence Scale for Children (WISC-R) and the Dutch version of the Child Behavior Checklist for ages 4-18 years (CBCL 4-18) and the Teacher Report Form (TRF)). Neurophysiological tests were performed using magnetoencephalography and electroencephalography. In adolescence (14-18 years) the behavior of 33 children was studied again (CBCL and TRF). And the levels of dioxins and dioxin-like PCBs (dl-PCBs) were measured in serum. RESULTS: At prepubertal age no association was found between perinatal dioxin exposure and verbal, performal and total IQ or with the Touwen's test for neuromotor development. There were behavioral problems associated with both prenatal and postnatal dioxin exposure. In adolescence there were problems associated with the current dioxin levels and dioxin-like-PCBs. Neurophysiological tests revealed clear negative dysfunction. An increase in latency time after a motion stimulus (N2b) of 13 ms (= a delay of 10%) is associated with the higher prenatal dioxin exposure. A similar delay was measured in testing cognitive ability by analyzing the odd ball measurements, N200 and P300, together with an amplitude decrease of 12 %. The delay is indicative of a defective myelinisation and the decrease in amplitude of a loss of neurons. CONCLUSION: We found effects on behavior in association with the perinatal dioxin exposure and in adolescence in association with the current dioxin levels. Neurophysiological testing is instrumental in the detection of effects of perinatal background levels of chemicals on brain development in normal, healthy children. The clinical, neurological and psychological tests commonly used are not sensitive enough to detect important effects.

Primary Carnitine (OCTN2) Deficiency Without Neonatal Carnitine Deficiency.

Although the diagnosis of a primary carnitine deficiency is usually based on a very low level of free and total carnitine (free carnitine: 1-5 µM, normal 20-55 µM) (Longo et al. 2006), we detected a patient via newborn screening with a total carnitine level 67 % of the normal value. At the age of 1 year, after interruption of carnitine supplementation for a 4-week period the carnitine profile was assessed and the free carnitine level had dropped to 10.4 µmol/l (normal: 20-55 µM) and total carnitine level had dropped to 12.7 µmol/l (normal: 25-65 µM). Transient carnitine deficiency was not likely anymore and DNA mutation analysis of the OCTN2 (SLC22A5) gene showed a homozygous c.136C>T (p.P46S) mutation, confirming the diagnosis of primary carnitine deficiency. We would like to emphasize that neonates with a primary carnitine deficiency might present with relatively high levels of total carnitine due to placental carnitine transfer, and also draw the attention to the importance of regular follow-up and the significance of genetic diagnostics in patients with a nonclassical presentation.

Medical-grade honey enriched with antimicrobial peptides has enhanced activity against antibiotic-resistant pathogens.

Honey has potent activity against both antibiotic-sensitive and -resistant bacteria, and is an interesting agent for topical antimicrobial application to wounds. As honey is diluted by wound exudate, rapid bactericidal activity up to high dilution is a prerequisite for its successful application. We investigated the kinetics of the killing of antibiotic-resistant bacteria by RS honey, the source for the production of Revamil® medical-grade honey, and we aimed to enhance the rapid bactericidal activity of RS honey by enrichment with its endogenous compounds or the addition of antimicrobial peptides (AMPs). RS honey killed antibiotic-resistant isolates of Pseudomonas aeruginosa, Staphylococcus epidermidis, Enterococcus faecium, and Burkholderia cepacia within 2 h, but lacked such rapid activity against methicillin-resistant S. aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. It was not feasible to enhance the rapid activity of RS honey by enrichment with endogenous compounds, but RS honey enriched with 75 µM of the synthetic peptide Bactericidal Peptide 2 (BP2) showed rapid bactericidal activity against all species tested, including MRSA and ESBL E. coli, at up to 10-20-fold dilution. RS honey enriched with BP2 rapidly killed all bacteria tested and had a broader spectrum of bactericidal activity than either BP2 or honey alone.

Depressive behaviour in children diagnosed with a mitochondrial disorder.

A higher incidence of depression has been described in adults with primary oxidative phosphorylation disease. We evaluated the psychological characteristics of eighteen non-retarded pediatric patients diagnosed with a disorder of the oxidative phosphorylation. We found significantly higher rate of withdrawn, depressive behaviour compared to population norm scores, to children with other types of inborn errors of metabolism and also in comparison to patients with Sotos syndrome. The occurrence of depressive behaviour showed no correlation with the degree of mitochondrial dysfunction. These findings support the hypothesis that mood disorders could be associated to abnormal cerebral energy metabolism.

[Summary of the practice guideline 'Erectile dysfunction' from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'Erectiele disfunctie' van het Nederlands Huisartsen Genootschap.

The Dutch College of General Practitioners recently published the practice guideline 'Erectile dysfunction'. The prevalence of erectile dysfunction increases with age. A lot of the men suffering from erectile dysfunction do not consult their general practitioner, or only do so after a lot of delay. It is recommended that inquiry about erectile dysfunction be made during routine follow-up consultations for co-morbid conditions.

Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events.

Cyclin A/cdk2 has a role in progression through S phase, and a large pool is also activated in G2 phase. Here we report that this G2 phase pool regulates the timing of progression into mitosis. Knock down of cyclin A by siRNA or addition of a specific cdk2 small molecule inhibitor delayed entry into mitosis by delaying cells in G2 phase. The G2 phase-delayed cells contained elevated levels of inactive cyclin B/cdk1. However, increased microtubule nucleation at the centrosomes was observed, and the centrosomes stained for markers of cyclin B/cdk1 activity. Both microtubule nucleation at the centrosomes and the phosphoprotein markers were lost with short-term treatment of the cdk1/2 inhibitor roscovitine but not the Mek1/2 inhibitor U0126. Cyclin A/cdk2 localized at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Thus G2 phase cyclin A/cdk2 controls the timing of entry into mitosis by controlling the subsequent activation of cyclin B/cdk1, but also has an unexpected role in coordinating the activation of cyclin B/cdk1 at the centrosome and in the nucleus.

Psychosocial, cognitive, and motor functioning in patients with suspected Sotos syndrome: a comparison between patients with and without NSD1 gene alterations.

The aim of this study was to investigate psychosocial, cognitive, and motor functioning in patients clinically suspected of Sotos syndrome and to examine differences between patients with deletions or mutations of the gene encoding nuclear SET domain-containing protein 1 (NSD1; the major cause of the syndrome) and those without such alterations. Twenty-nine participants (21 males, 8 females) clinically suspected of Sotos syndrome (mean age 11y 10mo [SD 10y 11mo], range 1y 10mo-48y 5mo) were divided into an NSD1 mutation group (n=12; 8 males, 4 females) and an NSD1 non-mutation group (n=17; 13 males, 4 females). Intelligence, behaviour problems, attention-deficit-hyperactivity disorder (ADHD) symptoms, temperament, adaptive behaviour, and motor functioning were assessed with an extensive test battery. Scores were compared with those of control groups, and scores of the two subgroups were compared with each other. The mean IQ in the 21 individuals tested was 76 (SD 16; range 47-105). High rates of behaviour problems were found and patients lagged 1y 7mo to 2y 7mo behind in aspects of adaptive behaviour. In comparison with a control group of patients with a learning disability, motor functioning was better. NSD1 mutation compared with NSD1 non-mutation patients showed easier temperament, and fewer NSD1 mutation patients scored in the clinical range for 'total behaviour problems' (3/11 vs 13/17), 'internalizing behaviour' (2/11 vs 11/17), and ADHD (0/9 vs 4/15).

Mutations in the NSD1 gene in patients with Sotos syndrome associate with endocrine and paracrine alterations in the IGF system.

OBJECTIVE: To investigate the effect of nuclear receptor Su-var, 3-9, enhancer of zeste, trithorax (SET) domain-containing protein 1 (NSD1) gene alteration in patients with Sotos syndrome on plasma IGFs and IGF-binding proteins (IGFBPs), as well as on the IGF/IGFBP system activity at the tissue level. DESIGN: Twenty-nine patients suspected of Sotos syndrome were divided into two groups: patients with heterozygous deletions or mutations in the NSD1 gene (NSD1(+/-)) (n=11) and subjects without (NSD1(+/+)) (n=18). Plasma samples (n=29) and skin fibroblasts (n=23) were obtained. The results of both groups were compared and related to reference values. METHODS: IGF-I, IGF-II, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6 levels were determined by RIAs. The mitogenic response of fibroblasts to IGFs was investigated by [methyl-(3)H]thymidine incorporation. IGFBP-3 levels in the culture media were measured by RIA. IGFBP-3 mRNA expression was determined by real time RT-PCR. RESULTS: NSD1(+/-) patients showed significantly altered levels of IGF-I (mean-1.2 SDS), IGF-II (-1.2), IGFBP-3 (-1.7), IGFBP-4 (-0.4), IGFBP-2 (+0.8) and IGFBP-6 (+1.5). The NSD1(+/+) patients did not differ from the reference, with the exception of the mean IGFBP-3 level (-1.3). Basal proliferation and mitogenic response to IGFs was diminished in NSD1(+/-) fibroblasts compared with NSD1(+/+) (basal, P=0.02; IGF-I, P<0.001; IGF-II, P=0.02). Compared with control fibroblasts, only the mitogenic response was diminished (basal, P=0.07; IGF-I, P=0.04; IGF-II, P=0.04). A trend of higher IGFBP-3 secretion after IGF-I stimulation (P=0.09) and 3.5-5 times higher mRNA expression of IGFBP-3 in basal conditions was found in NSD1(+/-) fibroblasts in comparison to controls. CONCLUSIONS: NSD1(+/-) patients show endocrine and paracrine changes in the IGF system. These changes may contribute to the abnormal growth pattern.

Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid-labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos syndrome.

OBJECTIVE: Sotos syndrome is an overgrowth syndrome of poorly understood aetiology. We investigated whether this syndrome is related to alterations in plasma insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), acid-labile subunit (ALS) and serum IGFBP-3 proteolysis. DESIGN: Based on clinical criteria, 32 patients with clinical characteristics of Sotos syndrome (median age 8.4 years, range 1.8-48.4) were categorised into three groups: typical (n = 10, group 1), dubious (n = 12, group 2) and atypical (n = 10, group 3). Blood samples were obtained from 29 patients. MEASUREMENTS: Plasma IGF-I, IGF-II, E-II (pro-IGF-II and E-domain fragments), IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6 and ALS were measured by specific radioimmunoassays (RIAs). Except for E-II immunoreactivity, the concentrations were compared with those of age references, and expressed as standard deviation scores (SDS). IGFBP-3 proteolysis was assessed by incubation of serum with [125I]-IGFBP-3, followed by gel electrophoresis and was then compared with that in normal serum and third trimester pregnancy serum. RESULTS: Patients in group 1 showed significantly reduced plasma levels of IGF-II (median -0.9 SDS; p = 0.01), IGFBP-4 (-0.5 SDS; p = 0.02) and IGFBP-3 (-1.0 SDS; p = 0.01). Mean IGFBP-3 proteolysis was higher than in normal standard serum (61% vs 37%; p < 0.01) but lower than in third trimester pregnancy serum (94%; p < 0.01). Plasma IGF-I showed a tendency towards low values (median -0.9 SDS; p = 0.09), IGFBP-6 and ALS a tendency towards elevated levels (median values +0.8 SDS; p = 0.07 and +2.3 SDS; p = 0.09), and IGFBP-2 was normal. The mean value of E-II immunoreactivity was 8.7 nmol/l, similar to that in pooled normal plasma (8.6 nmol/l). Plasma and serum parameters in groups 2 and 3 were similar to reference values with the exception of plasma IGFBP-3 (in groups 2 and 3 median < or = -1.1 SDS; p < or = 0.02) and ALS (in group 3 median +1.3 SDS; p < 0.01). CONCLUSIONS: Patients with typical Sotos syndrome show low plasma IGF-II, IGFBP-3, IGFBP-4, and increased proteolysis of IGFBP-3 in serum. The extent to which these findings are associated with the pathophysiology of Sotos syndrome remains uncertain.

[Three patients with gynaecomastia]. / Drie patiënten met gynaecomastie.

In three patients gynaecomastia was diagnosed: a 22-year-old man with concomitant thyrotoxicosis due to an extensively metastasized extragonadal choriocarcinoma, a 53-year-old man with hypogonadism due to Klinefelter's syndrome that was biochemically obscured due to medications leading to elevated prolactin levels, and a 62-year-old man with acromegaly and secondary hypogonadism due to a mixed prolactin and growth hormone secreting pituitary adenoma. Gynaecomastia calls for thorough evaluation.

High rates of multiple antibiotic resistance in Streptococcus pneumoniae from healthy children living in isolated rural communities: association with cephalosporin use and intrafamilial transmission.

OBJECTIVE: Streptococcus pneumoniae is one of the most clinically significant pathogens with emerging antibiotic resistance. We performed a surveillance study in isolated rural populations of healthy children to estimate the prevalence of pneumococcal resistance and to contrast factors that predict pneumococcal carriage with those that specifically predict resistant pneumococcal carriage. METHODS: The study was conducted in 1998 in 2 rural communities in Utah. Families were recruited directly for participation through community canvassing. Surveillance nasopharyngeal cultures were obtained from children who were younger than 8 years. Antibiotic usage and information on other potential risk factors were obtained from questionnaires and local pharmacy records. Resistance was determined by testing isolates for susceptibility to penicillin, cefaclor, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, and trovafloxacin. Selected resistant isolates were characterized further by serotyping, pulsed field gel electrophoresis, and Southern blot with DNA probes specific for the pneumococcal lytA gene and for antibiotic resistance genes. RESULTS: In April 1998, surveillance nasopharyngeal cultures were obtained from 368 children aged

Effect of chronic phenelzine treatment on REM sleep: report of three patients.

Antidepressants belonging to the class of monoamine oxidase inhibitors (MAOI) such as phenelzine have long been known to drastically suppress REM sleep. Sleep and the electroencephalogram (EEG) in sleep and waking were studied in three depressed patients at regular time intervals before, during and after 6 to 18 months of phenelzine treatment. While REM sleep was initially eliminated in all patients, short REM sleep episodes reappeared after three to six months of medication. Total sleep time and EEG slow-wave activity (SWA, spectral power within 0.75-4.5 Hz) in nonREM sleep (stages 1-4) were not changed. In contrast, EEG theta frequency activity (TFA, power within 4.75-8.0 Hz) during a 5-min wake interval recorded prior to the sleep episodes was initially enhanced, and tended to correlate negatively with the percentage of REM sleep (p =.06). This observation indicates that compensatory REM sleep mechanisms may occur in wakefulness during chronic MAOI treatment.