The profile of patients with venous leg ulcers: A systematic review and global perspective.

BACKGROUND: A holistic profile that includes demographic, medical history and wound characteristics of individuals with venous leg ulceration is lacking. Lack of such a profile negatively impacts the ability to develop interventions to improve patient outcomes. OBJECTIVES: To describe the profile of the patient population with venous leg ulceration from published observational (non-interventional) studies and to identify gaps in the knowledge base for future research in this area. METHODS: A systematic review of observational studies that included more than 50 patients, from any world region, of any age and in any care setting. RESULTS: twenty studies, involving 3395 patients, from all world regions met our criteria. Demographic characteristics were well reported and showed a female to male ratio of 1.2:1, average age of 47-65 years, high levels of co-morbidities including hypertension (53-71%) and diabetes (16-20%), and only one study reporting ethnicity. When reported, approximately 4-30% had high levels of depression. The average wound size was 18.6-43.39 cm2; mean wound duration was 13.8-65.5 months, mean number of recurrences was four. No study reported on demographic factors plus medical history plus wound characteristics together. CONCLUSION: a comprehensive, holistic profile of the population with VLU is lacking. There is a critical need for more comprehensive profiling to enable the development of targeted interventions to improve outcomes.

Single Centre Experience - Clinical Presentation and Frequency of Paediatric Diabetic Ketoacidosis (DKA) At Diagnosis over a 5-Year Period.

Type 1 diabetes (T1D) symptoms are subtle and easily overlooked. Delayed diagnosis can result in Diabetic ketoacidosis (DKA), a life threatening complication with lasting consequences. We sought to define the presenting features of T1D and DKA frequency, in children <15 years diagnosed in a single national tertiary centre, and identify predictive factors for DKA. A review of T1D incident cases was undertaken from 2008-2012 using the National Diabetes Register (ICDNR) and clinical case notes. Data were compared with a 1997/8 national study. We found DKA at presentation in 28.7 % of children and 15.5% had moderate/severe DKA. Commonest symptoms were polydipsia, polyuria, weight loss, and lethargy. Median symptom duration was 17 days. Clinical presentation was similar and frequency of DKA at T1D diagnosis remains high. The proportion with moderate/severe DKA is lower than the 25% previously reported (p=0.038). National monitoring and targeted action to reduce DKA at diagnosis is required.

The incidence of childhood type 1 diabetes in Ireland and the National Childhood Diabetes Register.

The incidence of Type 1 diabetes (T1D) in childhood and adolescence is increasing globally with few exceptions. To date limited conflicting data has been available regarding diabetes epidemiology in Ireland. We sought to determine the incidence of T1D in those aged under 15 years in the ROI by establishing a prospective national register of incident cases (Irish Childhood Diabetes National Registry (ICDNR)) using a standardised protocol which includes a measure of case ascertainment using capture-recapture methodology. In the period, 489 new cases were identified. All paediatric centres nationally participated. The directly standardised incidence rate was 27.5 per 100,000 per year (95% CIs: 24.0, 30.9) and 26.0 (95% CIs: 22.7, 29.3) in 2008 and 2009 respectively. The ICDNR is widely acceptable, it has confirmed a high incidence of T1D and is vital to monitor changes in disease incidence, optimise resource utilisation and diabetes management in the Irish population.

Home environment: association with hyperactivity/impulsivity in children with ADHD and their non-ADHD siblings.

OBJECTIVE: We wished to ascertain if there is an association between symptoms of attention-deficit/hyperactivity disorder (ADHD) and home environment in children with ADHD and non-ADHD siblings, controlling for other environmental measures. METHODS: 96 children with ADHD combined type (ADHD-CT) and their siblings participated in the study. Parent and teacher Conners' rating scales were completed and home environment was assessed using the middle childhood and early adolescent Home Observation for Measurement of the Environment (HOME). ADHD symptoms were assessed for correlation with HOME in children with ADHD-CT and non-ADHD siblings and multiple regression analysis was used to control for gender, socio-economic status, exposure to nicotine, exposure to alcohol in utero, birth weight, gestational age, pregnancy and perinatal risk factors. The presence of oppositional disorders was assessed for association with HOME score in those with ADHD-CT. The multiple regression analysis was repeated controlling for environmental factors and for oppositional disorders in those with ADHD-CT. Oppositional symptoms were assessed for correlation with HOME score in non-ADHD siblings. RESULTS: Teacher-rated hyperactive/impulsive scores correlated with HOME (r=-0.27, P < 0.01) in children with ADHD-CT. This association remained significant when other environmental factors and oppositional disorders were controlled for. Environmental factors and gender contributed to 30% of the variance of ADHD symptoms in ADHD-CT. Parent-rated hyperactive/impulsive scores also correlated with HOME (r=-0.28, P < 0.05) for non-ADHD siblings. An association between HOME and diagnosis of oppositional defiant disorder or conduct disorder was found for children with ADHD-CT and between HOME and oppositional symptoms in non-ADHD siblings. CONCLUSIONS: The home environment has a small but significant association with hyperactive/impulsive symptoms in children with ADHD-CT and non-ADHD siblings. This association remained when other environmental factors were taken into account. Oppositional symptoms are associated with home environment in ADHD-CT and in non-ADHD siblings.

Maternal smoking and alcohol consumption during pregnancy as risk factors for sudden infant death.

A population based case control study was conducted to examine alcohol consumption and maternal smoking during pregnancy and the risk of SIDS in an Irish population. Each SIDS case (n = 287) was compared with control infants (n = 832) matched for date and place of birth for infants born from 1994 to 2001. Conditional logistic regression was used to investigate differences between Cases and Controls establishing Odds Ratio's (OR) and 95% Confidence Intervals (CI). Mothers who smoked were 3 times more likely to have a SIDS Case, and a dose response effect was apparent, with mothers smoking 1-10 cigarettes/day OR 2.93 (CI 1.50-5.71), and those smoking > 10 cigarettes/day OR 4.36 (CI 2.50-7.61). More Case mothers consumed alcohol during pregnancy than Control mothers and, within drinkers, the amount of alcohol consumed was also greater (p < 0.05). A dose response with frequency of drinking was apparent. The adjusted odds ratio for those consuming alcohol in all three trimesters was 3.59 (CI:1.40-9.20). Both of these risk factors are modifiable and need to be incorporated into antenatal education from a SIDS point of view.

Thyroid dysfunction in Down's syndrome and screening for hypothyroidism in children and adolescents using capillary TSH measurement.

UNLABELLED: Thyroid dysfunction is more common in individuals with Down's syndrome (DS) than in the general population, whose clinical features can mask the presenting signs and symptoms of hypothyroidism. Biochemical screening is necessary; however, venepuncture may be difficult. AIMS: To assess the prevalence of thyroid dysfunction in children and adolescents with DS and the feasibility of screening for hypothyroidism using capillary dried blood spot thyroid stimulating hormone (TSH) from infancy. METHODS: 394 children (217 boys, 177 girls) were clinically assessed for thyroid dysfunction and 305 children (aged 4 months to 18.9 years) were screened for hypothyroidism by capillary whole blood TSH sample. RESULTS: Thyroid dysfunction was detected in 4.6%, with 50% unscreened since neonatal screening. Parents reported minimal distress by fingerprick screening. CONCLUSION: DS is associated with an increased prevalence of thyroid dysfunction, particularly in preschool children. Biochemical screening is essential and capillary whole blood TSH sampling for hypothyroidism is feasible, less invasive and acceptable.

Extended Experience of Lower Dose Sapropterin in Irish Adults with Mild Phenylketonuria.

Adherence to dietary and treatment recommendations is a long-standing concern for adults and adolescents with PKU and treating clinicians. In about 20-30% of PKU patients, Phe levels may be controlled by tetrahydrobiopterin (BH4) therapy. The European PKU 2017 Guidelines recommends treatment with BH4 for cases of proven long-term BH4 responsiveness, with a recommended dosage of Sapropterin 10-20 mg/kg/day.We report four young Irish patients with mild PKU, known to be BH4 responsive, who were treated with lower doses of Sapropterin for over 7 years.Case 1: Female, currently age 20. Genotype p. 165T/p/F39L, c.[194T>C]; [117C>G]. Newborn Phe: 851 µmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day to maintain Phe levels <400 µmol/L. Commenced on Sapropterin 400 mg (6.5 mg/kg/day) with increase in Phe tolerance to 800 mg/day.Case 2: Female, currently age 23. Genotype p. 165T/pF39L; c.[194T>C]; [117C>G]. Newborn Phe: 714 µmol/L. Pre-Sapropterin Phe tolerance: 700 mg Phe/day. Commenced on Sapropterin 400 mg (8 mg/kg/day) with increase in Phe tolerance to 800 mg/day.Case 3: Male, currently age 22. Genotype p. 165T/p.S349P; c.[194T>C][1045T>C]. Newborn Phe: 1,036 µmol/L. Pre-Sapropterin Phe tolerance: 600 mg Phe/day. Commenced on Sapropterin 400 mg (5.4 mg/kg/day). Increased to 1,600 mg Phe/day.Case 4: Female, currently age 29. Genotype p.R408W/p/p.Y414C; c.[1222C>T], [1241A>G]. Newborn Phe: 1,600 µmol/L. Pre-Sapropterin tolerance: 450 mg/day. Commenced on Sapropterin 400 mg (5.0 mg/kg/day). Increased to 900 mg Phe/day.Almost 7 years of surveillance for these four patients has shown that this dose of Sapropterin (range 5-8 mg/kg day) was well tolerated and effective with a significant response to treatment and a marked improvement in quality of life at these lower Sapropterin doses.

CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.

OBJECTIVE: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

The Stroke Activity Scale: results of a validity study.

PURPOSE: To establish the concurrent validity and time to complete of the Stroke Activity Scale (SAS) a recently developed stroke motor disability scale designed for use in a busy clinical setting. METHOD: Forty-one stroke patients with residual hemiplegia were recruited and assessed on a single occasion using both the SAS (five items) and modified Motor Assessment Scale (MMAS) (eight items) by a research physiotherapist. Performance was videotaped and assessed subsequently by a second physiotherapist. RESULTS: Pearson's correlation coefficient between the two measures was 0.91. The SAS was significantly quicker to complete than the MMAS (2.8 vs. 10.4 min, p < 0.0001). CONCLUSION: The SAS had high concurrent validity with the MMAS but was much quicker to complete and therefore more suitable for use in clinical environments where time is at a premium.

Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer.

Using the 21N polyclonal antibody, we immunohistochemically stained 314 primary breast carcinomas to identify those tumors overexpressing the c-erbB-2 oncoprotein and to ascertain the prognostic significance of this expression on disease-free and overall survival. Positive membrane staining was present in 52 (17%) of these carcinomas of which 7 (13%) were ductal carcinomas in situ. There was no significant relationship between c-erbB-2 positivity and (a) age at diagnosis, (b) menopausal status, (c) tumor size, (d) lymph node status, (e) estrogen receptor status, or (f) whether or not the patient had disseminated disease outside the axillary fields. However, c-erbB-2-positive tumors were significantly associated with poorer grade (P = 0.02). Patients who were positive for this oncoprotein had a shorter disease-free survival (P = 0.002) and reduced overall survival (P = 0.0001). Overexpression of this oncoprotein was predictive of a worse prognosis in lymph node-positive disease (P = 0.003) and in patients presenting with grade II tumors (P = 0.001). Stratifying the patients on the basis of estrogen receptor status suggested that c-erbB-2+/estrogen receptor-negative status was predictive of a poorer prognosis when compared with the other subgroups (P less than 0.001). Primary and recurrent tumor tissues were available from 42 of the 314 patients. Identical patterns of c-erbB-2 expression occurred in 95% of cases, arguing against a direct role for c-erbB-2 expression in the process of tumor dissemination. The high incidence of staining in ductal carcinomas in situ suggests that expression of this oncoprotein is an early event in tumorigenesis. Finally, multivariate analysis indicated that the c-erbB-2 oncoprotein was an independent prognostic indicator for overall survival in breast carcinoma patients.

Energetics of coupled Na+ and Cl- entry into epithelial cells of bullfrog small intestine.

Na+, K+ and Cl- concentrations (cij) and activities (aij), and mucosal membrane potentials (Em) were measured in epithelial cells of isolated bullfrog (Rana catesbeiana) small intestine. Segments of intestine were stripped of their external muscle layers, and bathed (at 25 degrees C and pH 7.2) in oxygenated Ringer solutions containing 105 mM Na+ and Cl- and 5.4 mM K+. Na+ and K+ concentrations were determined by atomic absorption spectrometry and Cl- concentrations by conductometric titration following extraction of the dried tissue with 0.1 M HNO3. 14C-labelled inulin was used to determine extracellular volume. Em was measured with conventional open tip microelectrodes, aiCl with solid-state Cl-selective silver microelectrodes and aiNa and aiK with Na+ and K+-selective liquid ion-exchanger microelectrodes. The average Em recorded was -34mV. ciNa, ciK and ciCl were 51, 105 and 52 mM. The corresponding values for aiNa, aiK and aiCl were 18, 80 and 33 mM. These results suggest that a large fraction of the cytoplasmic Na+ is 'bound' or sequestered in an osmotically inactive form, that all, or virtually all the cytoplasmic K+ behaves as if in free solution, and that there is probably some binding of cytoplasmic Cl-. aiCl significantly exceeds the level corresponding to electrochemical equilibrium across the mucosal and baso-lateral cell membranes. Earlier studies showed that coupled mucosal entry of Na+ and Cl- is implicated in intracellular Cl- accumulation in this tissue. This study permitted estimation of the steady-state transapical Na+ and Cl- electrochemical potential differences (deltamuNa and deltamuCl). deltamuNa (-7000 J . mol-1; cell minus mucosal medium) was energetically more than sufficient to account for deltamuCl (1000--2000 J . mol-1).

Validating the Orpington Prognostic Score in an Irish in-patient stroke population.

An accurate assessment of stroke severity and the ability to predict prognosis is important for determining rehabilitation needs and long term management of patients after stroke. The Orpington Prognostic Score (OPS) is a clinically derived stroke severity scale that can be used to stratify patients into different severity groups. The aim of this study was to validate the Orpington Prognostic Score (OPS) in an Irish in-patient stroke population. Fifty 'first stroke' patients (21 male, median age 72.5 [range 31-93] years) were assessed within two weeks following stroke onset. Subjects were stratified into mild, moderate and severe groups using previously established cut-offs for the OPS. Outcomes were determined prospectively and compared to initial severity groups. Patients in the severe group had a significantly increased chance of dying (Odds ratio [95%CI] 2.16 [1.72-2.72] and this persisted after adjustment for age and gender. Length of stay increased significantly with increasing stroke severity group (F ratio 7.0 p=0.0025) and this association remained after adjusting for age and gender. The odds of being discharged home or of being able to walk independently by time of discharge decreased significantly (all p<0.001) as stroke severity increased and adjusting for age and gender did not alter these associations. A higher OPS score within 2 weeks of stroke onset was significantly associated with longer length of stay, increased mortality, reduced mobility at discharge and a reduced likelihood of discharge home. The OPS is a valid measure of stroke severity in Irish stroke in-patients.

Guidelines for the medical management of Irish children and adolescents with Down syndrome.

Down syndrome (DS) is the most common chromosomal cause of developmental disability in Ireland. Children with DS have a high incidence of associated treatable medical disorders where early intervention carries a better outcome. Currently there are no agreed protocols for the screening and management of children and adults with DS in Ireland. A cross-sectional study of 394 children and adolescents was undertaken in the Eastern Regional Health Authority (ERHA) to assess the medical needs of children and adolescents with DS, in order to develop medical management guidelines. This study provides evidence-based data that children and adolescents with DS have a high incidence of treatable medical disorders, which supports the need for the medical management guidelines presented.

Ocular toxocariasis in schoolchildren.

Ocular toxocariasis in humans is typically a unilateral disease caused by second-stage larvae of the Toxocara species. Serological evidence of widespread infection in humans provides little information on clinical disease. There is only a single previous estimate of the prevalence of ocular toxocariasis (from Alabama). The present survey examined the extent of consultant-diagnosed toxocaral eye disease among a population of schoolchildren. More than 120,000 participants were surveyed by questionnaire and follow-up. Two sets of control subjects from the same school and from the same county were compared with persons who had ocular toxocariasis. The prevalence of consultant-diagnosed toxocaral eye disease was 6.6 cases per 100,000 persons when only cases regarded as definite by the consultant ophthalmologist were included. This increased to 9.7 cases per 100,000 persons when both definite and strongly suspected cases were included. Geophagia and a history of convulsion were associated with toxocaral eye disease in both of the case-control studies.

Effects of nifedipine and felodipine on adenosine and inosine release from the hypoxemic rat cerebral cortex.

The cerebral cortical cup technique has been used to study the effects of nifedipine and felodipine on adenosine and inosine release from the rat brain. After basal and hypoxia (8% 02)-evoked control levels of purine release had been established, these 1,4-dihydropyridine calcium antagonists were administered intraperitoneally (1 mg/kg). Both agents depressed basal levels of purine efflux and suppressed the hypoxia-evoked release of adenosine and inosine. An inhibition of the transporter that mediates purine efflux from brain cells is likely to account for the suppression of release from the cerebral cortex. A reduced release of adenosine into the interstitial space also explains the ability of both agents to block the increase in CBF evoked by hypoxic challenges.

Effects of deoxycoformycin on adenosine, inosine, hypoxanthine, xanthine, and uric acid release from the hypoxemic rat cerebral cortex.

The effects of the adenosine deaminase inhibitor, deoxycoformycin, on purine release from the rat cerebral cortex were studied with the cortical cup technique. Deoxycoformycin (5 and 500 micrograms/kg i.v.) enhanced the hypoxia/ischemia-evoked release of adenosine from the cerebral cortex, indicating a marked rise in the adenosine content of interstitial fluid in the cerebral cortex. Inosine and hypoxanthine release were attenuated at the higher dose of deoxycoformycin. Uric acid release into the cortical perfusates was enhanced at the higher dose level. These results demonstrate that low doses of deoxycoformycin can be used to elevate interstitial levels of adenosine in the brain during hypoxia, and to depress the formation of some of its metabolites. The elevation of hypoxia/ischemia-evoked adenosine levels can account for the previously reported potentiation of hypoxia-evoked increases in rat cerebral blood flow after deoxycoformycin administration. The potential therapeutic utility of these findings is discussed.

Increases in cerebral cortical perfusate adenosine and inosine concentrations during hypoxia and ischemia.

The cerebral cortical cup technique was used to monitor changes in adenosine and inosine levels in the rat cerebral cortex during periods of hypoxia, anoxia, or hemorrhagic hypotension. Basal levels of adenosine and inosine in cortical perfusates stabilized within 10 min at concentrations of 30-50 and 75-130 nM, respectively. Comparable levels were observed in normal CSF collected from the cisterna magna. Reductions in the oxygen content of the inspired air (14, 12, 8, and 5% oxygen) resulted in increases in the adenosine and inosine levels in the cortical perfusates, the magnitude of the increase being progressively more pronounced with greater reductions in the oxygen content. Cerebral anoxia/ischemia, induced by 100% nitrogen inhalation, caused a rapid increase in the adenosine and inosine contents of the cortical perfusates. Hemorrhagic hypotension (46.1 +/- 1.7 mm Hg) of 5 min duration did not result in an elevated adenosine or inosine release. The results suggest that interstitial fluid adenosine levels are likely to be in the low nM range in the normoxic animal and are capable of rapid increases during hypoxic or anoxic episodes. The findings support the adenosine hypothesis of CBF regulation.

Expression of the adenyl cyclase-encoding gene (cya) of Rhizobium meliloti F34: existence of two cya genes?

To gain insight into the role of cyclic AMP (cAMP) in Gram-negative soil bacteria, we have studied the expression of an adenyl cyclase-encoding gene 'cya' of Rhizobium meliloti F34. In both Escherichia coli and Bradyrhizobium japonicum, the gene is expressed from a promoter(s) contained on a 2.6-kb fragment of the cloned insert, which may indicate the presence of a functional 'cya' promoter or the coincidental presence of sequences which can function as promoters in these two species. The study of 'cya'-lac fusion activity in R. meliloti indicated that the 'cya' gene is not expressed at detectable levels and, thus, may not contribute to the modulation of cAMP levels under the growth conditions employed. R. meliloti strains carrying defined genomic mutations at the 'cya' locus were still capable of the synthesis of near wild-type levels of cAMP. These results suggest that the cloned 'cya' gene is not the key determinant responsible for cAMP synthesis under the culture conditions employed.

Organization of the adenyl cyclase (cya) locus of Rhizobium meliloti.

A cya-like gene encoding adenyl cyclase from Rhizobium meliloti was localized to a 0.8-kb PstI-EcoRI fragment by subcloning experiments. Experiments in Escherichia coli 'maxicells' identified a R. meliloti cya gene product of 28 kDa, which is significantly smaller than the corresponding protein from enteric bacteria. A control region for the expression of the cya gene in E. coli was found on an adjacent 2.6-kb BglII-BamHI sequence by insertional mutagenesis with Tn5 and phage MudI (ApR lac). The direction of transcription of the cya gene was also determined using a cya::MudIlac fusion. Promoter activity of this cya::lac fusion was not decreased when glucose was added to the culture. The R. meliloti cya gene is conserved among R. meliloti strains but no homology could be detected to other Rhizobium species or to E. coli in DNA hybridization experiments.

Cloning and nucleotide sequence of the phosphoenolpyruvate carboxylase-coding gene of Corynebacterium glutamicum ATCC13032.

As a first step in determining the importance of the anaplerotic function of phosphoenolpyruvate carboxylase (PEPC) in amino acid biosynthesis, the ppc gene coding for PEPC of Corynebacterium glutamicum ATCC13032 has been cloned by complementation of an Escherichia coli ppc mutant strain. PEPC activity encoded by the cloned gene is not affected by acetyl-CoA under conditions where the E. coli enzyme is strongly activated, whereas acetyl-CoA is able to relieve inhibition by L-aspartate used singly or in combination with alpha-ketoglutarate. Amplification of the ppc gene in a C. glutamicum lysine-excreting strain resulted in increased PEPC-specific activity and lysine productivity. The nucleotide sequence of a DNA fragment of 4885 bp encompassing the ppc gene has been determined. At the amino acid level, PEPC from C. glutamicum presents overall a high degree of similarity with corresponding enzymes from three different organisms. The location of some strictly conserved regions may have important implications for PEPC activity and allostery.