Protein S antibody as an adjunct therapy for hemophilia B.

ABSTRACT: Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation factor IX (FIX). Approximately 60% of pediatric patients with HB possess a severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy through the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant protein S (PS) inhibits activated FIX (FIXa). PS ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercially obtained plasma and plasma from pediatric patients with HB. We included 11 pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of the FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Furthermore, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB.

Corrigendum to ' Recurrent venous thromboembolism in hospitalized children with a history of prior venous thromboembolism: a report from the Children's Hospital-Acquired Thrombosis Consortium' [Research and Practice in Thrombosis and Haemostasis Volume 7, Issue 5, July 2023, 102139].

[This corrects the article DOI: 10.1016/j.rpth.2023.102139.].

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Enoxaparin Thromboprophylaxis in Children Hospitalized for COVID-19: A Phase 2 Trial.

BACKGROUND: Evidence regarding the safety and efficacy of anticoagulant thromboprophylaxis among pediatric patients hospitalized for coronavirus disease 2019 (COVID-19) is limited. We sought to evaluate safety, dose-finding, and preliminary efficacy of twice-daily enoxaparin as primary thromboprophylaxis among children hospitalized for symptomatic COVID-19, including primary respiratory infection and multisystem inflammatory syndrome in children (MISC). METHODS: We performed a phase 2, multicenter, prospective, open-label, single-arm clinical trial of twice-daily enoxaparin (initial dose: 0.5mg/kg per dose; max: 60mg; target anti-Xa activity: 0.20-0.49IU/mL) as primary thromboprophylaxis for children <18 years of age hospitalized for symptomatic COVID-19. Study endpoints included: cumulative incidence of International Society of Thrombosis and Haemostasis-defined clinically relevant bleeding; enoxaparin dose-requirements; and cumulative incidence of venous thromboembolism within 30-days of hospital discharge. Descriptive statistics summarized endpoint estimates that were further evaluated by participant age (±12 years) and clinical presentation. RESULTS: Forty children were enrolled and 38 met analyses criteria. None experienced clinically relevant bleeding. Median (interquartile range) dose to achieve target anti-Xa levels was 0.5 mg/kg (0.48-0.54). Dose-requirement did not differ by age (0.5 [0.46-0.52] mg/kg for age ≥12 years versus 0.52 [0.49-0.55] mg/kg for age <12 years, P = .51) but was greater for participants with MISC (0.52 [0.5-0.61] mg/kg) as compared with primary COVID-19 (0.48 [0.39-0.51] mg/kg, P = .010). Two children (5.3%) developed central-venous catheter-related venous thromboembolism. No serious adverse events were related to trial intervention. CONCLUSIONS: Among children hospitalized for COVID-19, thromboprophylaxis with twice-daily enoxaparin appears safe and warrants further investigation to assess efficacy.

Secondary thrombosis prevention practice patterns in pediatrics: Results of an international survey.

Background: Pediatric venous thromboembolism (VTE) rates continue to increase. Although most children present with transient provoking factors, some have persistent prothrombotic risks beyond the initial treatment period warranting secondary anticoagulation. Current pediatric VTE guidelines provide limited recommendations in this regard. Objectives: Our primary objective was to identify key influences on pediatric thrombosis physicians' decisions to initiate secondary anticoagulation. Methods: We targeted pediatric hematologists/oncologists internationally using Duration of Therapy for Thrombosis in Children, Children's Hospital Acquired Thrombosis consortium, and Venous Thromboembolism Network US pediatric subgroup membership rosters, who self-identified as primary outpatient thrombosis providers. Of 124 total surveys distributed, 61 complete surveys were evaluable. We defined secondary anticoagulation as anticoagulant use beyond the initial treatment period, on a daily basis (extended) or limited to periods of superimposed clinical risk factors (episodic). Results: Pediatric thrombosis physicians surveyed indicated that they prescribe secondary anticoagulation in <25% of children despite persistent risks. Among those who indicated use of secondary anticoagulation, the preferred modality was extended anticoagulation in children with a history of recurrent unprovoked VTE (98%), chronic central venous catheter (74%), and potent thrombophilia (73%). Episodic anticoagulation was preferred in children with a history of mild thrombophilia (54%). Respondents were more likely to prescribe secondary anticoagulation for adolescents as opposed to children <12 years old. Conclusions: Among pediatric thrombosis physicians surveyed, they perceived the prevalence of persistent prothrombotic risks to be high in children who have completed a course of anticoagulation for provoked VTE; however, estimated use of secondary anticoagulation was low. Studies involving real-world data are needed to further evaluate use of secondary anticoagulation in this setting.

Outcomes of Isolated Neutropenia Referred to Pediatric Hematology-Oncology Clinic.

BACKGROUND: Children with isolated neutropenia (absolute neutrophil count [ANC] <1500/µL) are frequently referred to pediatric hematology and oncology clinics for further diagnostic evaluation. Scant literature exists on interventions and outcomes for isolated neutropenia. We hypothesized that children will have resolution of their neutropenia without the need for intervention(s) by a pediatric hematologist and oncologist. METHODS: We performed a 5.5-year institutional review board-approved retrospective chart review of children referred to our pediatric hematology and oncology clinics for isolated neutropenia. Neutropenia was categorized as mild (ANC of 1001-1500/µL), moderate (ANC of 500-1000 µL), severe (ANC of 201-500/µL), or very severe (ANC of ≤200/µL). RESULTS: Among 155 children referred with isolated neutropenia, 45 (29%) had mild neutropenia, 65 (42%) had moderate neutropenia, 30 (19%) had severe neutropenia, and 15 (10%) had very severe neutropenia. Only 29 (19%) children changed to an ANC category lower than their initial referral category. At a median follow-up of 12 months, 101 children had resolution of neutropenia, 40 children had mild neutropenia, 10 children had moderate neutropenia, 3 children had severe neutropenia, and 1 patient had very severe neutropenia. A specific diagnosis was not identified in most (54%) children. The most common etiologies were viral suppression (16%), autoimmune neutropenia (14%), and drug-induced neutropenia (8%). Black children had a 3.5 higher odds of having persistent mild neutropenia. Six (4%) children received granulocyte colony-stimulating factor therapy. CONCLUSIONS: Most children referred for isolated neutropenia do not progress in severity and do not require subspecialty interventions or hospitalizations.

Thermal Conductivity of the Iron-Based Superconductor FeSe: Nodeless Gap with a Strong Two-Band Character.

The thermal conductivity κ of the iron-based superconductor FeSe was measured at temperatures down to 75 mK in magnetic fields up to 17 T. In a zero magnetic field, the electronic residual linear term in the T=0 K limit, κ_{0}/T, is vanishingly small. The application of a magnetic field B causes an exponential increase in κ_{0}/T initially. Those two observations show that there are no zero-energy quasiparticles that carry heat and therefore no nodes in the superconducting gap of FeSe. The full field dependence of κ_{0}/T has the classic two-step shape of a two-band superconductor: a first rise at very low field, with a characteristic field B^{⋆}≪B_{c2}, and then a second rise up to the upper critical field B_{c2}. This shows that the superconducting gap is very small (but finite) on one of the pockets in the Fermi surface of FeSe. We estimate that the minimum value of the gap, Δ_{min}, is an order of magnitude smaller than the maximum value, Δ_{max}.

Comparison of chemometric methods for the screening of comprehensive two-dimensional liquid chromatographic analysis of wine.

Two chemometric methods are compared for the rapid screening of comprehensive two-dimensional liquid chromatographic (LC×LC) analysis of wine. The similarity index and Fisher ratio methods were both found to be able to distinguish geographical variability and to determine potentially significant peaks for further quantitative and qualitative study. An experimental data set consisting of five different wine samples and multiple simulated data sets were analyzed in the investigation of the screening methods. Several statistical analyses are employed in the understanding and verification of the results from the similarity index and Fisher ratio methods. The sum rank difference (SRD) method was used to compare the rankings of the two different methods as applied to the different data sets and to determine the amount of variability associated with the ranking of the peak differences. The major advantage the similarity index method offers is that it is an unsupervised method; no a priori knowledge of the samples (i.e., class identification) is required, while the Fisher ratio method is supervised. Both methods are rapid and require little user intervention other than the determination of a threshold for inclusion/exclusion of compounds from further analysis.

Chemometric analysis of targeted 3DLC-DAD data for accurate and precise quantification of phenytoin in wastewater samples.

A variety of pharmaceuticals have been found in various water systems, including wastewater treatment effluent. Due to the possible environmental and human health implications, it is important to be able to quickly and reliably quantify the amount of pharmaceuticals and personal care products that may be present in such samples. To this end, a new chromatographic analysis technique involving three dimensions of liquid chromatography, including selective comprehensive separations in the second and third dimensions, was applied to the analysis of a wastewater treatment plant effluent (WWTPE) sample using both standard addition and external calibrations. Iterative key set factor analysis alternating least squares with the application of both sample and spectral selectivity constraints was used to resolve the phenytoin peak at a concentration corresponding to about 40 parts-per-trillion using UV absorbance detection. Both the precision and accuracy of the method are investigated. We determined that the concentration of phenytoin in WWTPE using selective three dimensional liquid chromatography with diode array detection was 42 ± 1 ng/L, after resolution from an unknown interferent. The estimated concentration was not significantly different from that obtained by the reference 2DLC/MS/MS method, but was four and a half times more precise.

Factors that affect quantification of diode array data in comprehensive two-dimensional liquid chromatography using chemometric data analysis.

There has been a tremendous increase in research on comprehensive two dimensional LC (LC×LC); however, to date, the central analytical issue, quantification, has received only minimal attention. It is vital to the further development of LC×LC that a greater understanding of the specific factors affecting peak quantification in LC×LC be attained. This work focuses on the following factors: data complexity, retention time shifting, dynamic range issues, chromatographic and spectral peak overlap and difficulties related to background signal removal. The above mentioned factors that affect peak quantification are investigated using fourteen replicate analyses of a urine sample, representing the effects of such factors when analyzing samples in complex matrices. We demonstrate that quantification of LC×LC data is improved following implementation of chemometric techniques that minimized the deleterious effects on quantification due to chromatographically overlapped peaks, retention time shifting and background signal interference. The chemometrically resolved data shows a 2.5-fold increase in precision of quantification over the quantification of the raw data. It is also demonstrated that the method quantifies sixteen peaks that were not visually evident prior to chemometric analysis. The purpose of this paper is to determine the impact of these issues on the effectiveness of LC×LC as a technique for the quantitative analysis of complex samples.

Chemometric Resolution and Quantification of Four-Way Data Arising from Comprehensive 2D-LC-DAD Analysis of Human Urine.

Two-dimensional liquid chromatography (LC×LC) is quickly becoming an important technique for the analysis of complex samples, owing largely to the relatively high peak capacities attainable by this analytical technique. With the increase in the complexity of the sample comes a corresponding increase in the complexity of the collected data. Thus the need for chemometric methods capable of resolving and quantifying such data is ever more urgent in order to obtain the maximum information available from the data. To this end, we have developed a chemometric method that combines iterative key set factor analysis and multivariate curve resolution-alternating least squares analysis with a spectral selectivity constraint that is shown to be capable of resolving chromatographically rank deficient, non-multilinear data. (Spectrally rank deficient compounds can only be quantified if the peaks having the same spectra are chromatographically resolved.) Over 50 chromatographic peaks were found in a relatively small section of a LC×LC-diode array data set of replicate urine samples (a four-way data set) using the developed method. The relative concentrations for 34 of the 50 peaks were determined with % RSD values ranging from 0.09 % to 16 %.

The usefulness of ultrasound assessment of amniotic fluid in predicting adverse outcome in prolonged pregnancy: a prospective blinded observational study.

OBJECTIVE: To determine whether a single ultrasound scan at or beyond 40 weeks of gestation to detect a single deepest pool of amniotic fluid <2 cm and amniotic fluid index (AFI) <5 cm is clinically useful in the prediction of subsequent adverse pregnancy outcome. DESIGN: A prospective double blind cohort study. SETTING: A university teaching hospital delivering approximately 6000 women annually. POPULATION: One thousand and five hundred and eighty-four pregnant women at or beyond 40 weeks of gestation. METHODS: Ultrasound assessment of liquor to detect the single deepest pool of amniotic fluid and derive the AFI at or after 40 weeks of gestation. MAIN OUTCOME MEASURES: Perinatal death, meconium aspiration, birth asphyxia, intervention in labour for fetal distress, a cord arterial pH <7 and admission to the neonatal unit. RESULTS: An AFI <5 cm but not a single deepest pool <2 cm was significantly associated with birth asphyxia or meconium aspiration. An AFI <5 cm was also significantly associated with caesarean section for fetal distress in labour, a cord arterial pH <7 at delivery and low Apgar scores. Despite there being a statistically significant association with adverse outcomes the sensitivity of AFI was low at 28.6%, 12% and 11.5% for major adverse outcome, fetal distress in labour or admission to the neonatal unit, respectively. CONCLUSIONS: The AFI is superior to a measure of the single deepest pool as an assessment of the fetus at or after 40 weeks but has a poor sensitivity for adverse pregnancy outcome. Routine use is likely to lead to increased obstetric intervention without improvement in perinatal outcomes.

Outcome at school age following antenatal detection of absent or reversed end diastolic flow velocity in the umbilical artery.

AIM: To determine whether fetal compromise, manifested by abnormalities of Doppler recordings of umbilical artery velocity waveforms in utero, is associated with neurodevelopmental or educational abnormalities at school age. METHODS: A cohort of neonates born following high risk pregnancies had been previously identified for a study of the perinatal sequelae of absent (AEDFV) and reversed (REDFV) end diastolic flow velocities. Seventy six children were assessed at 5-12 years of age by a developmental paediatrician who was blinded to perinatal course and Doppler assessments. Forty children born following pregnancies with forward end diastolic flow velocities (FEDFV), were compared with 27 with AEDFV and nine with REDFV. Tests of cognitive, neurological, and sensory function were performed, and reports of behavioural and educational progress were obtained from parents and teachers. RESULTS: There were no significant differences between FEDFV and AEDFV groups, but on tests of mental ability and neuromotor function the REDFV group had worse scores than either FEDFV or AEDFV. Comparing REDFV and FEDFV groups, the British Ability Scales general conceptual ability mean scores were 87.7 versus 101, and the Quick Neurological Screening Test mean scores were 32.8 versus 21.5. CONCLUSIONS: Absence of EDFV is well recognised as a marker of fetal compromise which is associated with acute perinatal sequelae. This study suggests it is not associated with adverse neurodevelopmental outcome. However, we found reversal of EDFV on antenatal assessment to be associated with a wide range of problems at school age, suggesting that REDFV represents intrauterine decompensation which may have adverse effects on the developing brain.

Randomized, controlled trial of acetazolamide and furosemide in posthemorrhagic ventricular dilation in infancy: follow-up at 1 year.

OBJECTIVE: Posthemorrhagic ventricular dilation (PHVD) is a complication of intraventricular hemorrhage in preterm infants and is associated with a high risk of long-term disability. Furosemide and acetazolamide are used widely in the treatment of PHVD in the hope of avoiding the need for placement of a ventriculoperitoneal shunt, but these drugs have not been evaluated in a controlled trial. This article reports a multicenter, randomized, controlled trial designed to test the hypothesis that these drugs would reduce the rate of shunt placement (or death) and increase survival to 1 year of age without disability. METHODS: Between 1992 and 1996, 177 infants who were less than 3 months past term and had ventricular width >4 mm above the 97th centile following intraventricular hemorrhage were assigned randomly to either standard therapy or standard therapy plus drug therapy with acetazolamide (100 mg/kg/d) plus furosemide (1 mg/kg/d). Infants who were enrolled in the trial had a median gestational age of 28.6 weeks and were enrolled at a mean postnatal age of 3.6 weeks. Forty-four percent were reported to have a cerebral parenchymal lesion on ultrasound scan at randomization. The primary outcome measure of death or shunt placement (known in all but 1 infant) occurred in 56 of 88 infants who were allocated to drug plus standard therapy compared with 46 of 88 who were allocated to standard therapy. The risk ratio was 1.23 (95% confidence interval: 0.95-1.59). Neurodevelopmental outcome information at a corrected age of 1 year (known in all but 3 of 149 surviving infants) included disability or neuromotor impairment in 54 of 67 infants (81%) who were allocated to drug plus standard therapy and 52 of 69 infants (66%) who were allocated to standard therapy. Seventy-two of 85 infants (85%) who were allocated to drug therapy either died or were disabled or impaired at 1 year compared with 62 of 89 infants (70%) who were treated with standard therapy (risk ratio: 1.22; 95% confidence interval: 1.03-1.4376). The excess risk of these adverse outcomes was greater among infants who did not have a cerebral parenchymal lesion seen on ultrasound examination at trial entry. CONCLUSIONS: These results suggest that the use of acetazolamide and furosemide in preterm infants with PHVD is ineffective in decreasing the rate of shunt placement and is associated with increased neurologic morbidity. This treatment therefore cannot be recommended.

Educational and behavioural problems in babies of 32-35 weeks gestation.

AIM: To identify incidence of school and behaviour problems at age 7 years in children born between 32 and 35 weeks gestation, and investigate perinatal risk factors. METHOD: The study population consisted of all children born at 32-35 weeks gestation to mothers resident in Oxfordshire in 1990. General practitioners, parents, and teachers were asked about health, behaviour, and education by postal questionnaire. Teachers rated children on level of function in six areas using a five point scale. They also completed the Strengths and Difficulties behaviour questionnaire. Perinatal risk factors were identified for children with poor school performance using a univariate and multivariate analysis. RESULTS: Teacher responses were obtained for 117 (66%) of the 176 children in the cohort. Twenty nine (25%) required support from a non-teaching assistant, five (4%) had required a statement of special educational needs, and three (3%) were at special school. Poor outcome was reported for 32% in writing, 31% in fine motor skills, 29% in mathematics, 19% in speaking, 21% in reading, and 12% in physical education. On the behaviour questionnaire, 19% of the cohort achieved an abnormal hyperactivity score (population norm 10%). Multivariate analysis showed perinatal variables that remained significant, independent of other variables; they were discharge from the special care baby unit > 36 weeks postconceptional age (odds ratio 4.15; 95% confidence interval 1.43 to 12.05) and male sex (odds ratio 3.88; 95% confidence interval 1.42 to 10.6). CONCLUSION: Up to a third of children born between 32 and 35 weeks gestation may have school problems. As there are larger numbers in this gestational category compared with smaller babies, this finding has implications for educational services.

Cloning of leptin cDNA and assignment to the long arm of chromosome 5 in the marsupial Sminthopsis crassicaudata.

We have isolated and sequenced full-length cDNA clones for leptin in the dasyurid marsupial Sminthopsis crassicaudata (fat-tailed dunnart). Southern and in situ hybridisation data indicated a single leptin gene in the S. crassicauda- ta genome, localised to arbitrary chromosome bands 5q24--> q31 on the long arm of chromosome 5, the short-arm terminus of which bears the only nucleolar organising region. The nucleotide sequence of the cDNAs revealed that the primary translation product of S. crassicaudata leptin is composed of 167 amino acid residues, with a potential signal peptide of 21 residues. The mature protein of 146 amino acids is 82% similar to both the mouse and human proteins and is predicted to have a molecular weight of 16.26 kDa. Northern blot analysis revealed that the corresponding mRNA is approximately 3.9 kb in size and is expressed only in white adipose tissue of this marsupial species. Evolutionary analyses indicate that S. crassicaudata leptin cDNA has evolved at a significantly faster rate than cDNAs from eutherian mammals.

The effect of ovarian steroids and photoperiod on body fat stores and uncoupling protein 2 in the marsupial Sminthopsis crassicaudata.

To determine the effects of photoperiod and ovarian steroids on fat stores in the marsupial S. crassicaudata, animals were ovariectomised (OVX) or sham operated, and maintained under either short-day (SD) or long-day (LD) photoperiods for 104 days. Photoperiod had no effect on body weight in the sham animals. In the LD OVX animals, body weight fell and remained below baseline for about 45 days, whereafter it returned to baseline. In contrast, body weight of SD OVX animals increased over the first 45 days then returned to baseline. Tail width (a reflection of body fat stores) increased in both sham and OVX animals exposed to SD. When exposed to LD, tail width increased only in the OVX animals. There was no effect of either photoperiod or OVX on total cumulative energy intake. Leptin mRNA expression was increased in the LD OVX animals compared to the shams. Photoperiod had no effect on UCP2 mRNA expression in any tissue; however, OVX decreased UCP2 mRNA expression in muscle. These data indicate that in S. crassicaudata: (a) fat mass increases in response to both SD photoperiod and OVX and they have additive effects; (b) the effects of photoperiod on fat mass are mediated by both gonadal steroid dependent and independent mechanisms; (c) alterations in UCP2 mRNA expression may mediate the effect of OVX, but not photoperiod; and (d) UCP2 mRNA is differentially regulated in muscle and fat.

Peripheral administration of CRF and urocortin: effects on food intake and the HPA axis in the marsupial Sminthopsis crassicaudata.

The hypothalamic peptides corticotrophin releasing factor (CRF) and urocortin (UCN) decrease food intake and increase energy expenditure when administered either centrally or peripherally to rodents. The effects of CRF and UCN on food intake in other mammals (for example marsupials), however, are not known. Peripherally administered CRF induced cortisol release in the marsupial Sminthopsis crassicaudata via the CRF1 receptor, and central CRF administration potently decreased food intake, as in rodents. When peripherally administered, both CRF and UCN decreased food intake in S. crassicaudata, but UCN was considerably more potent ( approximately 50 fold) in this regard. The anorectic effects of CRF and UCN were not blocked by the CRF1 receptor antagonist antalarmin, suggesting that the peripheral effects of CRF and UCN on food intake are mediated primarily by the CRF2 receptor.

Corticomotor excitability and perception of effort during sustained exercise in the chronic fatigue syndrome.

OBJECTIVE: We have investigated the possibility of a central basis for the complaints of fatigue and poor exercise tolerance in subjects with chronic fatigue syndrome (CFS). METHODS: Transcranial magnetic stimulation of the motor cortex was used to measure sequential changes in motor evoked potential (MEP) amplitude, post-excitatory silent period (SP) duration and twitch force of the biceps brachii muscle during a 20% maximum isometric elbow flexor contraction maintained to the point of exhaustion. Ten patients with post-infectious CFS and 10 age- and sex-matched control subjects were studied. Results were analysed using non-parametric repeated measures analysis of variance (Friedman's test) and Mann-Whitney U-tests for intra- and inter-group comparisons respectively. RESULTS: Mean endurance time for the CFS group was lower (13.1+/-3.2 min, mean +/- SEM) than controls (18.6+/-2.6 min, P < 0.05) and CFS subjects reported higher ratings of perceived exertion. During the exercise period MEP amplitude and SP duration increased in both groups but to a lesser extent in CFS subjects. Interpolated twitch force amplitude also increased during exercise, being more pronounced in CFS subjects. CONCLUSION: The findings are in keeping with an exercise-related diminution in central motor drive in association with an increased perception of effort in CFS.