Altered autonomic control of heart rate variability in the chronically hypoxic fetus.

KEY POINTS: Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established. The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV. In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy. We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans. Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected. ABSTRACT: Although fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, the mechanisms by which it is reduced in the chronically hypoxic fetus have yet to be established. In particular, the physiological mechanism underlying the reduction of short term variation (STV) in fetal compromise remains unclear. In this study, we present a longitudinal study of the development of autonomic control of FHRV, assessed by indirect indices, time domain and power spectral analysis, in normoxic and chronically hypoxic, chronically catheterised, singleton fetal sheep over the last third of gestation. We used isobaric chambers able to maintain pregnant sheep for prolonged periods in hypoxic conditions (stable fetal femoral arterial PO2 10-12 mmHg), and a customised wireless data acquisition system to record beat-to-beat variation in the fetal heart rate. We determined in vivo longitudinal changes in overall FHRV and the sympathetic and parasympathetic contribution to FHRV in hypoxic (n = 6) and normoxic (n = 6) ovine fetuses with advancing gestational age. Normoxic fetuses show gestational age-related increases in overall indices of FHRV, and in the sympathetic nervous system contribution to FHRV (P < 0.001). Conversely, gestational age-related increases in overall FHRV were impaired by exposure to chronic hypoxia, and there was evidence of suppression of the sympathetic nervous system control of FHRV after 72 h of exposure to hypoxia (P < 0.001). This demonstrates that exposure to late gestation isolated chronic fetal hypoxia has the potential to alter the development of the autonomic nervous system control of FHRV in sheep. This presents a potential mechanism by which a reduction in indices of FHRV in human fetuses affected by uteroplacental dysfunction can predict fetuses at increased risk.

Expert opinion: Stepwise ultrasound assessment of suspected placenta accreta spectrum using 2D, Doppler and 3D imaging.

Placenta Accreta Spectrum (PAS) describes a spectrum of conditions ranging from 'sticky' placenta to placenta accreta, increta and percreta-each describing progressively deeper invasion into the uterus. It is a major contributor to maternal and perinatal morbidity particularly where clinical facilities are not immediately available. Hence accurate diagnosis is important in determining timing and place of delivery, and logistical arrangements of the clinical team and specialties. Although many different ultrasound features have been described, their relationship to the final operative diagnosis remains variably described. Ultrasound manufactures have developed new imaging techniques particularly in relation to Doppler and 3D processing techniques. We describe a standardized imaging approach employing new ultrasound modalities matched to the attributes unique to invasive placenta. The '3V' system describes the stages of placental invasion: namely low-flow Doppler techniques to delineate the vascular anatomy of the placenta and delineating its interface with the myometrium, and 3D 'context preserving' post processing technologies defining the placental interface with maternal structures (vesicular invasion and visceral extension). Used together with well characterized 2D imaging signs, we describe pictorially by reference to clinical cases how this standardized methodology allows new insights into the ultrasound diagnosis of PAS.

Expectant management versus multifetal pregnancy reduction in dichorionic triamniotic (DCTA) triplets: Single centre experience.

OBJECTIVES: In trichorionic triplet pregnancies, multifetal pregnancy reduction (MFPR) reduces the risk of preterm birth, neonatal morbidity and mortality without increasing miscarriage. A similar benefit has been suggested in dichorionic triamniotic (DCTA) pregnancy, but multiple methods are currently used. This study investigates if the method of reduction used in DCTA triplet pregnancy influences the evidence of benefit from MFPR. METHODS: This is a retrospective cohort study of DCTA pregnancies between 2010 and 2019 who attended a single UK fetal medicine tertiary referral center. Cohorts were defined based on MFPR decision and method. The primary outcome was offspring survival until neonatal discharge. The secondary outcomes included miscarriage, preterm birth, livebirth, rates of small for gestational age (SGA) neonates, ans maternal morbidity. To evaluate the differences in neonatal survival until discharge we used Cox proportional regression to calculate hazard rates (HR) and 95% confidence intervals (CI). Differences in secondary outcomes were compared using univariate analysis. RESULTS: The study reports the outcomes for 83 DCTA pregnancies. MFPR to DCDA twins was chosen in 19 pregnancies (14 radiofrequency ablation, RFA; 5 intrafetal laser, IFL); in 9 pregnancies selective reduction to a singleton was performed by KCl injection. The rate of pregnancies in with ≥ 1 fetus born alive was not different between groups (p = 0.90). However, the number of expected neonates alive at discharge from hospital was highest in the RFA group (89%, HR 0.28, 95% CI 0.21-0.87, p = 0.02). Rates of premature delivery before 32 weeks (p = 0.02), low birth weight (p < 0.001) and birthweight < 10th percentile (p = 0.01) were all elevated in the expectant management group, compared to women who opted for reduction. There was no difference in miscarriage between groups. CONCLUSIONS: Our study suggests that MFPR by RFA, an established and widely available procedure, is of benefit in promoting neonatal survival until discharge in DCTA triplets.

Efficacy of Hylan G-F 20 and Sodium Hyaluronate in the treatment of osteoarthritis of the knee -- a prospective randomized clinical trial.

In this independent prospective randomized trial, we compared the clinical effectiveness, functional outcome and patient satisfaction following intra articular injection with two viscosupplementation agents - Hylan G-F-20 (n=199) and Sodium Hyaluronate (n=193) in patients with osteoarthritis (OA) of the knee. All patients were prospectively reviewed by blinded independent assessors at pre injection, 6 weeks, 3, 6, 12 months. Knee pain and patient satisfaction were measured on a visual analogue scale. Functional outcome was assessed using WOMAC, Oxford knee score and EuroQol EQ-5D scores. Knee pain on VAS improved from 6.7 to 3.2 by 6 weeks (p=0.02) and was sustained until 12 months (3.7, p=0.04) with Hylan G-F 20. In the Sodium Hyaluronate group, pain improved from 6.6 to 5.7 at 6 weeks (p>0.05) and to 4.1 at 3 months (p=0.04) but was sustained only until 6 months (5.9, p>0.05). Improvement in the WOMAC pain subscale was significantly superior in the Hylan G-F 20 group at 3 months (p=0.02), 6 months (p=0.01) and 12 months (p=0.007). There was no significant difference in the EQ-5D scores at 6 weeks and 3 months between the two groups. The numbers of treatment related adverse events were higher (39 vs. 30) in the Hylan G-F 20 group. One patient in the Hylan G-F 20 group who had a serious adverse event was also included in the final analysis. Although both treatments offered significant pain reduction, it was achieved earlier and sustained for a longer period with Hylan G-F 20. From this study, it appeared that the clinical effectiveness and general patient satisfaction are better amongst patients who received Hylan G-F 20.

Comparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders.

BACKGROUND: Proximal chromosome 17p is a region rich in low copy repeats (LCRs) and prone to chromosomal rearrangements. Four genomic disorders map within the interval 17p11-p12: Charcot-Marie-Tooth disease type 1A, hereditary neuropathy with liability to pressure palsies, Smith-Magenis syndrome, and dup(17)(p11.2p11.2) syndrome. While 80-90% or more of the rearrangements resulting in each disorder are recurrent, several non-recurrent deletions or duplications of varying sizes within proximal 17p also have been characterised using fluorescence in situ hybridisation (FISH). METHODS: A BAC/PAC array based comparative genomic hybridisation (array-CGH) method was tested for its ability to detect these genomic dosage differences and map breakpoints in 25 patients with recurrent and non-recurrent rearrangements. RESULTS: Array-CGH detected the dosage imbalances resulting from either deletion or duplication in all the samples examined. The array-CGH approach, in combination with a dependent statistical inference method, mapped 45/46 (97.8%) of the analysed breakpoints to within one overlapping BAC/PAC clone, compared with determinations done independently by FISH. Several clones within the array that contained large LCRs did not have an adverse effect on the interpretation of the array-CGH data. CONCLUSIONS: Array-CGH is an accurate and sensitive method for detecting genomic dosage differences and identifying rearrangement breakpoints, even in LCR-rich regions of the genome.

Antiandrogens do not reverse androgen-induced inhibition of sex hormone-binding globulin levels in adult female rhesus monkeys.

Studies were done to determine if changes in plasma sex hormone-binding globulin (SHBG) levels could serve as a specific marker of androgenic and antiandrogenic activities in rhesus monkeys. Treatment of adult female monkeys for 11 days with 17 alpha-methyltestosterone (MeT) produced dose and time-dependent reductions in SHBG levels. However, the non-steroidal antiandrogen flutamide (80 mg/monkey.day) did not inhibit the reduction in SHBG levels when coadministered with MeT, nor did it have an effect on SHBG levels when given alone. In contrast, the steroidal antiandrogens Win 49596 (100 mg/monkey.day) and cyproterone acetate (80 mg/monkey.day) significantly (P less than 0.01) reduced SHBG plasma concentration to about 50% of pretreatment control values whether given alone or in combination with MeT. Furthermore, Win 49596 reduced SHBG levels at doses as low as 4 mg/monkey, whereas cortico-steroid-binding globulin levels were not affected. In ovariectomized monkeys, MeT treatment (4 mg/monkey.day for 15 days) reduced plasma SHBG levels to 42% of pretreatment values and delayed the onset of withdrawal menstrual bleeding compared to that in controls. When administered concurrently with MeT, flutamide (100 mg/monkey.day) antagonized the effect on withdrawal bleeding, but was without effect on SHBG levels. Therefore, plasma SHBG levels cannot be used as a specific indicator of androgenic or antiandrogenic activity and may not be regulated through the classical androgen receptor.

The donor chromosome breakpoint for a jumping translocation is associated with large low-copy repeats in 21q21.3.

Jumping translocations (JTs) are very rare chromosome aberrations, usually identified in tumors. We report a constitutional JT between donor chromosome 21q21.3-->qter and recipients 13qter and 18qter, resulting in an approximately 15.5-Mb proximal deletion 21q in a girl with mild developmental delay and minor dysmorphic features. Using fluorescence in situ hybridization (FISH) studies, we identified an approximately 550-kb complex inter- and intra-chromosomal low-copy repeat (LCR) adjacent to the 21q21.3 translocation breakpoint. On the recipient chromosomes 13qter and 18qter, the telomeric sequences TTAGGG were retained. Genotyping revealed that the deletion was of maternal origin. We propose that genome architecture involving LCRs may be a major mechanism responsible for the origin of jumping translocations.

Determination of sialic acids by liquid chromatography-mass spectrometry.

Sialic acids are widely found in nature as components of oligosaccharide units in mucins, glycoproteins and other microbial polymers. Existing methods for determining these acids are long, tedious, and not specific. A simple, rapid, and sensitive method for determining the most commonly occurring acids, N-acetylneuraminic and N-glycolylneuraminic acid, using LC-MS is described. Standard solutions of the sialic acids with the internal standard, N-acetylneuraminic acid methyl ester, were quantitatively analyzed by positive ion electrospray ionization. Fetuin was used as a model glycoprotein and the hydrolysate was injected directly onto an ES Industries AquaSep 3 microm 150x4.6 mm column eluted with a 0.1% aqueous formic acid mobile phase at a flow-rate of 0.5 ml/min. Detection was achieved using the Finnigan Navigator MS system in the selected ion monitoring mode for the protonated molecular ions at m/z 310, 324, and 326. The linearity over the dynamic range 10 to 1000 ng of sialic acids on-column had a correlation coefficient greater than 0.999. The amount of sialic acids found in the fetuin hydrolysate was in agreement with values reported in the literature.

Characterization of a synthetic peptide impurity by fast-atom bombardment-tandem mass spectrometry and gas chromatography-mass spectrometry.

Fast-atom bombardment-tandem mass spectrometry (FAB-MS-MS) was used to characterize the structure of atosiban, a synthetic oxytocin antagonist, and one of its synthesis-related impurities. The nature of the structural modification in the impurity of interest, replacement of the proline residue by 5-aminovaleric acid, was determined directly from its product ion MS-MS spectrum. Confirmation of the identity of the impurity was accomplished with GC-MS.

Characterization of the degradation products of luteinizing hormone releasing hormone.

The degradation products of luteinizing hormone releasing hormone [LH/RH; 1; gonadorelin releasing hormone (GnRH); less than Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2] were determined in aqueous solution (pH 6.5) at 25, 37, 50, and 80 degrees C. The predominant route of degradation involved the cleavage of the less than Glu-His and Trp-Ser peptide bonds to give peptides 5-9 and hydrolysis of the terminal Gly-NH2 to the free acid form in peptides 4 and 10. Racemization of the serine and histidine residues to give peptides 2 and 3 was a second route of degradation.

Characterization of the solution degradation products of histrelin, a gonadotropin releasing hormone (LH/RH) agonist.

The degradation products of histrelin (1, less than Glu-His-Trp-Ser-Tyr-(D-Nim-bzl-His)-Leu-Arg-Pro-NHEt) were determined in aqueous solution at pH 5.4 and 87 degrees C over an 18-day period (47% degradation). These degradation products (2-5) resulted from the cleavage of less than Glu-His and Trp-Ser peptide bonds, His-Trp diketopiperazine formation, and racemization of serine and histidine residues.

Successful laparoscopic repair of a traumatic pubic symphysis hernia.

A 48-year-old woman presented with a hernia through the center of her pubic symphysis 6 months after conservative treatment of an open-book fracture of the pelvis. This was repaired laparoscopically with a prosthetic mesh using a transperitoneal approach. Hernia through the pubic symphysis is a rare complication after traumatic symphysis diastasis, but repair using the laparoscopic approach is feasible and associated with rapid recovery from surgery.

A direct HPLC method for the resolution of glycidyl tosylate and glycidyl 3-nitrobenzenesulphonate enantiomers.

The enantiomeric composition of glycidyl tosylate and glycidyl 3-nitrobenzenesulphonate is obtained using an enantiomeric HPLC column. The chiral oxiranes were resolved on a cellulose carbamate column using a mobile phase of hexane:2-propanol. The method is simple, sensitive and does not require derivatization.

Fungal osteomyelitis of the foot. A report of an unusual case.

Mucormycosis is an opportunistic infection that very occasionally causes osteomyelitis and avascular necrosis of bone. The infection may prove fatal if not diagnosed promptly. If early treatment is instituted the prognosis is good.

Screening for diabetic retinopathy in a clinical setting: a comparison of direct ophthalmoscopy by primary care physicians with fundus photography.

BACKGROUND: Type II diabetes mellitus is a major health problem among Native Americans, and diabetic retinopathy is a frequent complication of this disease. Screening for retinopathy can identify early disease and prevent major vision loss, but the most cost-effective screening method has not yet been determined. METHODS: In a rural clinic that served more than 400 Native Americans with diabetes, we compared the accuracy of referrals made based on two screening methods: ophthalmoscopy by trained primary care physicians and seven-view nonstereoscopic, mydriatic fundal photography read by two general ophthalmologists and a retinal specialist. Patients in whom abnormal findings were detected by either screening method were then referred to a general ophthalmologist for further evaluation. RESULTS: Two hundred forty-three examinations were performed and 83 referrals made. Both screening methods had high sensitivity for referring patients with retinopathy that required treatment or follow-up sooner than 1 year (100% for direct ophthalmoscopy by primary care physicians, 94% for the general ophthalmologist photography readers, and 100% for the retinal specialist reader). The calculated costs of screening by direct ophthalmoscopy and by retinal photography were 64% less and 44% to 35% less, respectively, than the cost of yearly ophthalmological examinations by ophthalmologists. CONCLUSIONS: Careful screening for treatable diabetic eye disease by trained primary care physicians proved to be a clinically acceptable, cost-effective strategy. Screening methods for diabetic retinopathy should be evaluated based on the absolute sensitivity, specificity, and predictive values of their ability to correctly refer patients rather than their diagnostic accuracy.

Percutaneous pulsed lavage for the infected knee replacement.

The low incidence of infection in knee arthroplasty is in sharp contrast to the high morbidity associated with its occurrence. This lends urgency to the need for early diagnosis and prompt management when infection does appear. To add to the armamentarium of the existing modalities in dealing with this condition, a new technique is described, which allows lavage at high pressure through a minimal access approach. It has been used successfully in two cases, though the follow-up was less than two years. A long-term follow-up will allow us to judge if this technique, used for the correct indications, can promote the longevity of the prosthesis threatened by infection.

The relationship between hospital readmissions of medicare beneficiaries with chronic illnesses and home care nursing interventions.

A retrospective audit of the charts of 62 Medicare patients with diagnoses of congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) was conducted. Data that described marital status, number of visits made, number of hospital readmissions, and types of nursing interventions were collected. A significant relationship was found between certain nursing interventions and hospital readmissions.

Pathophysiological mechanisms of high-intensity focused ultrasound-mediated vascular occlusion and relevance to non-invasive fetal surgery.

High-intensity focused ultrasound (HIFU) is a non-invasive technology, which can be used occlude blood vessels in the body. Both the theory underlying and practical process of blood vessel occlusion are still under development and relatively sparse in vivo experimental and therapeutic data exist. HIFU would however provide an alternative to surgery, particularly in circumstances where serious complications inherent to surgery outweigh the potential benefits. Accordingly, the HIFU technique would be of particular utility for fetal and placental interventions, where open or endoscopic surgery is fraught with difficulty and likelihood of complications including premature delivery. This assumes that HIFU could be shown to safely and effectively occlude blood vessels in utero. To understand these mechanisms more fully, we present a review of relevant cross-specialty literature on the topic of vascular HIFU and suggest an integrative mechanism taking into account clinical, physical and engineering considerations through which HIFU may produce vascular occlusion. This model may aid in the design of HIFU protocols to further develop this area, and might be adapted to provide a non-invasive therapy for conditions in fetal medicine where vascular occlusion is beneficial.

The cost of outpatient venous thromboembolism prophylaxis following lower limb injuries.

This paper reports the cost of outpatient venous thromboembolism (VTE) prophylaxis following 388 injuries of the lower limb requiring immobilisation in our institution, from a total of 7408 new patients presenting between May and November 2011. Prophylaxis was by either self-administered subcutaneous dalteparin (n = 128) or oral dabigatran (n = 260). The mean duration of prophylaxis per patient was 46 days (6 to 168). The total cost (pay and non-pay) for prophylaxis with dalteparin was £107.54 and with dabigatran was £143.99. However, five patients in the dalteparin group required nurse administration (£23 per home visit), increasing the cost of dalteparin to £1142.54 per patient. The annual cost of VTE prophylaxis in a busy trauma clinic treating 12 700 new patients (2010/11), would be £92 526.33 in the context of an income for trauma of £1.82 million, which represents 5.3% of the outpatient tariff. Outpatient prophylaxis in a busy trauma clinic is achievable and affordable in the context of the clinical and financial risks involved.