Intermittent mydriasis associated with carotid vascular occlusion.

PurposeTo describe two cases of stereotyped, intermittent, neurologically isolated, unilateral mydriasis in patients with a history of acquired internal carotid artery (ICA) occlusive disease on the ipsilateral side.PatientsTwo patients with intermittent mydriasis.MethodsCase Series.ResultsCase one: A 78-year-old man experienced 10 episodes of intermittent, unilateral, and painless mydriasis in the left eye and had 100% occlusion of the left ICA artery due to atherosclerotic disease. Case two: A 26-year-old woman with history of migraine developed new painless, intermittent episodes of unilateral mydriasis after sustaining chest trauma and was diagnosed with subsequent dissection and 65% occlusion of the ipsilateral ICA. Neither patient developed permanent anisocoria.ConclusionBenign episodic unilateral mydriasis (BEUM) typically presents in young women with a history of migraine. To our knowledge, these are the first cases of episodic, unilateral, neurologically isolated mydriasis associated with occlusive disease of the ICA in the English language ophthalmic literature. We hypothesize that transient dysfunction of the autonomic nervous system related to the ICA disease may account for the intermittent mydriatic episodes in these patients and we recommend consideration for imaging of the ICA in patients with atypical features for BEUM (for example, old age or males, non-isolated mydriasis, or recent trauma).

A whole system approach to improving mortality associated with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is in the main managed by non-nephrologists, many who feel challenged by or lack awareness of the complexity that the renal element adds to their patients' care. National reports have raised major concerns about the quality of care and have predicted that mortality reductions of 30% are achievable with good medical practice. AIM: This quality improvement project evaluated whether a whole system approach could improve outcomes for patients with AKI. DESIGN AND METHODS: Quality improvement methodology was used to understand hospital patterns, processes and professional knowledge. Change concepts were developed which included management of patients at risk, staff education and awareness program, development of a patient specific electronic alert to prompt diagnosis, easy to remember care bundle (ABCDE-IT), dedicated outreach team and patient and family empowerment leaflet. RESULTS: Statistical process control analysis was used to verify outcomes over time. A shift in the in-hospital mortality rate corresponded to a relative 23.2% reduction in mortality and was sustained over the next 33 months (P < 0.0001). The favourable shift in mortality was temporally distinct from the improved AKI detection rate. This timeframe corresponded to lying below the 99.8% lower confidence limit in comparison with all English acute trusts for comparative AKI specific SHMI/HSMR mortality rates. Length of stay also reduced shortly after onset of the project by 14.1% or 2.6 day reduction (P < 0.0001). CONCLUSION: This project demonstrated that an integrated, whole-system approach is necessary to ensure sustained improvements in AKI mortality and length of stay.

A Holstein cow-calf model for the transfer of ciprofloxacin through milk after a long-term intravenous infusion.

This study is part of an ongoing effort to develop animal models that provide milk and sufficient infant (offspring) plasma samples to fully describe a drug's pharmacokinetics to quantitate the risk to the nursing infant. Ciprofloxacin was administered to six healthy Holstein cows as a constant rate intravenous infusion (flow rate was weight adjusted) to achieve a steady-state concentration of approximately 300 ng/mL for 7 days. Plasma and milk samples were collected from the cow at regular intervals over the course of the 7 days. The plasma and milk samples were analyzed for ciprofloxacin by high-performance liquid chromatography. The milk was fed to calves, and calf plasma samples were analyzed to study the lactational transfer of ciprofloxacin from dam to nursing neonate. Remarkably, concentrations of ciprofloxacin in milk were 45 times higher than plasma drug concentrations in the dam. Approximately 6% of the administered dose was transferred to the milk, resulting in an average oral dose of 0.5 mg/kg to the calves with every feeding. The drug did not accumulate in the calves, and plasma concentrations were between one-tenth and one-fifth the plasma concentrations of the dam.

The evolution of prenatal screening and diagnosis and its impact on an unselected population over an 18-year period.

OBJECTIVE: To review changes in and impact of prenatal screening and diagnosis. DESIGN: Population-based congenital anomaly register study. SETTING: Oxfordshire. POPULATION: Congenital anomalies confirmed and those suspected prenatally, delivered 1991-2008. METHODS: Analysis of proportions of congenital anomalies confirmed and those suspected prenatally. MAIN OUTCOME MEASURES: Birth prevalence, prenatal detection rates, pregnancy outcomes. RESULTS: A total of 2651 (2.3%) infants/fetuses had a congenital anomaly diagnosed. There were 3839 suspected or confirmed cases, 2847 due to a prenatal suspicion, of which 1659 had an anomaly confirmed at delivery, and 1188 false-positive diagnoses, 91% due to reporting ultrasound normal variants. The percentage of prenatal notifications rose from 48% in 1991-93 to 83-88% from 1996 to 2003 and dropped to 61% in 2006-08, partly reflecting changes in the reporting of normal variants. Reporting these increased the prenatal diagnosis rate from 53 to 63% with an increase in false-positive rate from 0.09 to 1.04%. A total of 722 (44% of prenatally detected affected fetuses) resulted in termination; 48% of these had chromosome anomalies, 34% had isolated structural anomalies, 7% had multiple anomalies, 10% had familial disorders; 42% had lethal anomalies and 58% would probably have survived the neonatal period giving an estimated 20% reduction in birth prevalence of congenital anomalies compatible with survival because of terminations. CONCLUSION: There has been an improvement in prenatal detection of congenital anomalies over the two decades studied. The recognition that reporting normal variants, although increasing prenatal detection rates, leads to an increase in false-positive diagnoses has had an impact on practice that has redressed the balance between these two effects.

Intra- and interobserver variability in fetal ultrasound measurements.

OBJECTIVE: To assess intra- and interobserver variability of fetal biometry measurements throughout pregnancy. METHODS: A total of 175 scans (of 140 fetuses) were prospectively performed at 14-41 weeks of gestation ensuring an even distribution throughout gestation. From among three experienced sonographers, a pair of observers independently acquired a duplicate set of seven standard measurements for each fetus. Differences between and within observers were expressed in measurement units (mm), as a percentage of fetal dimensions and as gestational age-specific Z-scores. For all comparisons, Bland-Altman plots were used to quantify limits of agreement. RESULTS: When using measurement units (mm) to express differences, both intra- and interobserver variability increased with gestational age. However, when measurement of variability took into account the increasing fetal size and was expressed as a percentage or Z-score, it remained constant throughout gestation. When expressed as a percentage or Z-score, the 95% limits of agreement for intraobserver difference for head circumference (HC) were ± 3.0% or 0.67; they were ± 5.3% or 0.90 and ± 6.6% or 0.94 for abdominal circumference (AC) and femur length (FL), respectively. The corresponding values for interobserver differences were ± 4.9% or 0.99 for HC, ± 8.8% or 1.35 for AC and ± 11.1% or 1.43 for FL. CONCLUSIONS: Although intra- and interobserver variability increases with advancing gestation when expressed in millimeters, both are constant as a percentage of the fetal dimensions or when reported as a Z-score. Thus, measurement variability should be considered when interpreting fetal growth rates.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable treatment risks may differ considerably from the ones in case of less serious disease. This theme was the focus of the international conference "Taking immunogenicity assessment of therapeutic proteins to the next level", held at the Paul-Ehrlich-Institut in Langen, Germany, on the 10-11. June 2010. The objectives of the conference were to highlight how the field could move from that of a mere description of risk factors to a system of risk assessment and mitigation, as well as an understanding of the impact of unwanted immunogenicity on the overall benefit/risk consideration for a medicinal product. More than 150 experts from industry, academia and regulatory authorities worldwide discussed the phenomenon of undesired immunogenicity from different perspectives. The conference focussed on issues relevant to three areas: (1) new European guidelines that are currently the subject of discussion; (2) testing strategies for immunogenicity assessment; and (3) scientific progress on the product-related factors that may contribute to the development of pathogenesis of immunogenicity, in particular in the field of protein aggregation and post-translational modifications. This report provides an overview of issues, insights, and conclusions that were discussed and achieved during the meeting.

An engineered solution to the maladministration of spinal injections.

BACKGROUND: An overview is provided of the progress made in a Department of Health (DH) initiative to implement an engineered solution to the maladministration of spinal injections. In an effort to eliminate the possibility of misconnection errors at the spinal route, the DH is investigating the potential for dedicated spinal equipment that will be incompatible with standard Luer syringes, needles and associated devices. METHOD: Background information on the problem of misconnection errors is provided and a systematic approach to their eradication is detailed. Research to date has entailed extensive bench-testing of prototype non-Luer connectors, a prospective hazard analysis of spinal procedures in haematology and anaesthesia and usability evaluation of prototype non-Luer devices in simulated environments. RESULTS: The prospective hazard analysis identified two potential risks which will need to be managed as part of a successful implementation programme. CONCLUSION: Usability testing of two prototype connection systems concluded that one design was inadequate, as the non-Luer element was provided as a separable adapter. The second connection system was modified following the first round of testing, and achieved improved satisfaction ratings from clinicians in round two. This system was selected to proceed to a pre-implementation evaluation and the research team are currently evaluating its acceptability in clinical use.

Prenatal diagnosis of tracheo-oesophageal fistula and oesophageal atresia.

OBJECTIVES: To assess the accuracy of the prenatal ultrasound finding of subjectively small/absent stomach bubble in the prenatal diagnosis of tracheo-oesophageal fistula and oesophageal atresia (TOF/OA). METHODS: A retrospective study of prenatal ultrasound scans showing small/absent stomach bubble was carried out between 1st January 1994 and 31st December 2003. RESULTS: There were 62 cases with prenatally suspected (n = 40) and/or post-natally diagnosed (n = 22) TOF/OA. Among the 40 cases of prenatally suspected TOF/OA 15 were thought to be isolated and 25 non-isolated. Of the 15 suspected isolated cases, 7 were normal and 8 had TOF/OA (5 isolated + 3 TOF/OA with another anomaly) at delivery. Among the 25 cases of prenatally suspected non-isolated TOF/OA, there was confirmation in only two cases, in the remaining 23 cases other anomalies were confirmed but TOF/OA was not present.Twenty-two babies with TOF/OA were identified in whom there had been no prenatal ultrasound suspicion on ultrasound scanning. Six had isolated TOF/OA and 16 had non-isolated TOF/OA. CONCLUSION: Of the 32 cases of confirmed TOF/OA,10 (31%) were suspected prenatally. If the TOF/OA was an isolated anomaly (11 cases), the prenatal detection rate was 45%. Interpretation of ultrasound findings suspicious of TOF/OA requires caution, particularly, when there are associated multiple anomalies on scan.

Congenital myotonic dystrophy: prenatal ultrasound findings and pregnancy outcome.

OBJECTIVE: The objective of this study was to assess the maternal and prenatal ultrasound findings and outcome in pregnancies complicated by congenital myotonic dystrophy Type 1 (DM1). METHODS: A retrospective chart review of all patients with a diagnosis of DM1 and pregnancy presenting to the Oxford Radcliffe Hospital between 1990 and 2004 was undertaken. Obstetric case notes were reviewed and details of all pregnancies obtained. This included data on prenatal diagnostic tests and obstetric ultrasound scans performed as well as pregnancy complications and pregnancy outcome. Maternal and fetal CTG expansion size was also recorded where available. Maternal genetic case notes were reviewed for details of maternal grip myotonia. RESULTS: Sixty pregnancies among 26 couples in which one of the parents was a carrier of DM1 were identified during the study period. These resulted in 36 (60%) pregnancies affected by congenital DM1 and 19 (31.7%) unaffected pregnancies. There were four miscarriages and one termination of pregnancy for non-medical reasons. Nineteen of the 36 affected pregnancies ended in termination following the antenatal diagnosis of congenital DM1 by either chorionic villus sampling (CVS) or amniocentesis. In the remaining 17 affected pregnancies (16 singleton and one twin) there was one miscarriage of an affected fetus with co-existing Down syndrome and eight perinatal deaths. The principal cause of perinatal death was respiratory failure in the early neonatal period. Antenatally noted clinical/sonographic abnormalities in these pregnancies included polyhydramnios (100%), talipes (26.6%) and borderline ventriculomegaly (13.3%). Uni- or bilateral talipes was noted at delivery in 10 of 16 (62.5%) neonates. Maternal grip myotonia was present in all but one of these cases. CONCLUSION: The antenatal findings of polyhydramnios and talipes should prompt a search for maternal grip myotonia. If present, definitive testing for congenital DM1 should be considered.

Outcome of antenatally suspected congenital cystic adenomatoid malformation of the lung: 10 years' experience 1991-2001.

OBJECTIVE: To determine the outcome of antenatally suspected congenital cystic adenomatoid malformation of the lung (CCAM) over a 10 year period. METHODS: This is a retrospective study of all babies diagnosed antenatally in the Prenatal Diagnosis Unit and delivered in Oxford between 1991 and 2001. Data were obtained from the Oxford Congenital Anomaly Register, theatre records, and histopathology reports. RESULTS: Twenty eight cases of CCAM were diagnosed antenatally. Five pregnancies were terminated. Data are available on all 23 of the pregnancies that continued and resulted in two neonatal deaths and 21 surviving babies. Eleven of the 23 cases (48%) showed some regression of the lesion antenatally, and four of these cases appeared to resolve completely on prenatal ultrasound. Three of the 23 babies (13%) were symptomatic in the early neonatal period, and three developed symptoms shortly afterwards. Seventeen of the 23 babies (74%) were asymptomatic, of whom 12 had abnormalities on chest radiograph or computed tomography scan and had elective surgery. Two babies (8%) had completely normal postnatal imaging, and three had abnormalities which resolved in the first year of life. Seventeen of the 23 babies (74%) had surgery. Histology at surgery was heterogeneous. Of the 23 live births, all 21 survivors (91%) are well at follow up or have been discharged. CONCLUSIONS: All babies diagnosed antenatally with CCAM require postnatal imaging with computed tomography irrespective of signs of antenatal resolution. In asymptomatic infants, the recommendations are close follow up and elective surgery for persistent lesions within the first year of life. Histology at surgery was heterogeneous, and this should be considered when counselling parents.

Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors.

Leu100Ile, Val106Ala and Val108Ile are mutations in HIV-1 reverse transcriptase (RT) that are observed in the clinic and give rise to resistance to certain non-nucleoside inhibitors (NNRTIs) including the first-generation drug nevirapine. In order to investigate structural mechanisms of resistance for different NNRTI classes we have determined six crystal structures of mutant RT-inhibitor complexes. Val108 does not have direct contact with nevirapine in wild-type RT and in the RT(Val108Ile) complex the biggest change observed is at the distally positioned Tyr181 which is > 8 A from the mutation site. Thus in contrast to most NNRTI resistance mutations RT(Val108Ile) appears to act via an indirect mechanism which in this case is through alterations of the ring stacking interactions of the drug particularly with Tyr181. Shifts in side-chain and inhibitor positions compared to wild-type RT are observed in complexes of nevirapine and the second-generation NNRTI UC-781 with RT(Leu100Ile) and RT(Val106Ala), leading to perturbations in inhibitor contacts with Tyr181 and Tyr188. Such perturbations are likely to be a factor contributing to the greater loss of binding for nevirapine compared to UC-781 as, in the former case, a larger proportion of binding energy is derived from aromatic ring stacking of the inhibitor with the tyrosine side-chains. The differing resistance profiles of first and second generation NNRTIs for other drug resistance mutations in RT may also be in part due to this indirect mechanism.

Follow-up of children with isolated fetal echogenic bowel with particular reference to bowel-related symptoms.

OBJECTIVES: To determine whether there was any evidence of long-term bowel pathology in children, apparently healthy at birth, who had a prenatal second-trimester diagnosis of isolated grade 2 fetal echogenic bowel. METHODS: This was a retrospective study using data from the Oxford Congenital Anomaly Register. Fetuses with isolated grade 2 fetal echogenic bowel and date of delivery from 1994 to 2000 inclusive were identified. Information about the health of the children, particularly relating to bowel symptoms, was obtained from hospital records and from a questionnaire sent to the general practitioner. RESULTS: A total of 109 cases were identified, with delivery details available for 108. There was one unexplained intrauterine death, and additional problems were subsequently diagnosed in four cases (cystic fibrosis (2), Down syndrome (1), and VACTERL (1)). Questionnaires were sent to the GPs of the 103 who had no problems identified at the time of discharge from the maternity hospital. Age at follow-up ranged from one to four years. Responses to the questionnaires were received from 83 (81%). Of these, 74 (89%) had not reported bowel symptoms to the GP, 9 (11%) reported symptoms relating to constipation (6), chronic abdominal pain (1), infantile colic with milk intolerance (1) and gastro-oesophageal reflux (1). CONCLUSION: This small study provides some reassurance that there was no evidence of any serious long-term bowel pathology associated with isolated fetal echogenic bowel.

Autopsy after termination of pregnancy for fetal anomaly: retrospective cohort study.

OBJECTIVE: To study trends in termination of pregnancy for fetal anomaly over 10 years and to assess the contribution of autopsy to the final diagnosis and counselling after termination. DESIGN: Retrospective study with cases from a congenital anomaly register and a defined unselected population. DATA SOURCES: Pregnancies resulting in termination for fetal anomaly identified from the Oxford congenital anomaly register. Details about the prenatal diagnosis and autopsy findings were retrieved from case notes. RESULTS: Of the 57 258 deliveries, 309 (0.5%) were terminated because of prenatally diagnosed abnormality. There were 129/29 086 (0.4%) terminations for fetal anomaly carried out in 1991-5 and 180/28 172 (0.6%) in 1996-2000. The percentage of fetuses that underwent autopsy fell from 84% to 67%. Autopsy was performed in 132 cases identified by ultrasound scan, with no evidence for abnormal karyotype. In 95 (72%) the autopsy confirmed the suspected diagnosis and did not add important further information, two cases were not classified, and in 35 (27%) the autopsy added information that led to a refinement of the risk of recurrence (reduced in 17, increased in 18); in 11 of these 18 cases it was increased to a one in four risk. CONCLUSIONS: Though there has been an increase in the rate of terminations of pregnancy for fetal anomaly, there has been a decline in the autopsy rate. When a prenatal diagnosis was based on the results of a scan only, the addition of information from an autopsy by a specialist paediatric pathologist provided important information that changed the estimated risk of recurrence in 27% of cases and in 8% this was to a higher (one in four) risk.

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.

An overview of scientific and regulatory issues for the immunogenicity of biological products.

Immunogenicity of biological products can occur pre-clinically and clinically when products elicit immune responses in animals or humans receiving the products. This is a concern for manufacturers, regulatory agencies and clinicians as immune responses can result in effects on product effectiveness and safety. The clinical sequelae of immunogenicity range from no effects to serious, life-threatening syndromes. However, although many biological products are immunogenic to some extent, it is quite rare that immunogenicity leads to serious adverse events. Whilst there are methods to detect immunogenicity, they currently rely on detecting the humoral rather than the cellular response of the immune system. The design and validation of assays such as immuno-assays and bio-assays are critical for a meaningful assessment of immunogenicity. There are a growing number of computational and laboratory-based methods for the prediction of immunogenicity, as well as methods to reduce potential immunogenicity and these may lead to less immunogenic biological products in future.

Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors.

The HIV-2 serotype of HIV is a cause of disease in parts of the West African population, and there is evidence for its spread to Europe and Asia. HIV-2 reverse transcriptase (RT) demonstrates an intrinsic resistance to non-nucleoside RT inhibitors (NNRTIs), one of two classes of anti-AIDS drugs that target the viral RT. We report the crystal structure of HIV-2 RT to 2.35 A resolution, which reveals molecular details of the resistance to NNRTIs. HIV-2 RT has a similar overall fold to HIV-1 RT but has structural differences within the "NNRTI pocket" at both conserved and nonconserved residues. The structure points to the role of sequence differences that can give rise to unfavorable inhibitor contacts or destabilization of part of the binding pocket at positions 101, 106, 138, 181, 188, and 190. We also present evidence that the conformation of Ile-181 compared with the HIV-1 Tyr-181 could be a significant contributory factor to this inherent drug resistance of HIV-2 to NNRTIs. The availability of a refined structure of HIV-2 RT will provide a stimulus for the structure-based design of novel non-nucleoside inhibitors that could be used against HIV-2 infection.

Crystal structures of Zidovudine- or Lamivudine-resistant human immunodeficiency virus type 1 reverse transcriptases containing mutations at codons 41, 184, and 215.

Six structures of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) containing combinations of resistance mutations for zidovudine (AZT) (M41L and T215Y) or lamivudine (M184V) have been determined as inhibitor complexes. Minimal conformational changes in the polymerase or nonnucleoside RT inhibitor sites compared to the mutant RTMC (D67N, K70R, T215F, and K219N) are observed, indicating that such changes may occur only with certain combinations of mutations. Model building M41L and T215Y into HIV-1 RT-DNA and docking in ATP that is utilized in the pyrophosphorolysis reaction for AZT resistance indicates that some conformational rearrangement appears necessary in RT for ATP to interact simultaneously with the M41L and T215Y mutations.