Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis

Objective: Early treatment in sepsis may improve outcome. The aim of this study was to evaluate how the delay in starting resuscitation influences the severity of sepsis and the treatment needed to achieve hemodynamic stability. Design: Prospective, randomized, controlled experimental study. Setting: Experimental laboratory in a university hospital. Subjects: Thirty-two anesthetized and mechanically ventilated pigs. Interventions: Pigs were randomly assigned (n = 8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48-hr period of protocolized resuscitation started 6 (Delta T-6 hrs), 12 (Delta T-12 hrs), or 24 (Delta T-24 hrs) hrs later. The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction. Measurements and Main Results: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-alpha prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1 +/- 0.5 mL/kg/hr, 2.8 +/- 0.7 mL/kg/hr, and 3.2 +/- 1.5 mL/kg/hr, respectively, for groups.T-6 hrs, Delta T-12 hrs, and.T-24 hrs; p < .01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02 +/- 0.04 mu g/kg/min, 0.06 +/- 0.09 mu g/kg/min, and 0.13 +/- 0.15 mu g/kg/min; p = .059), decreased maximal brain mitochondrial complex II respiration (p = .048), and tended to increase mortality (p = .08). Muscle tissue adenosine triphosphate decreased in all groups (p < .01), with lowest values at the end in groups Delta T-12 hrs and.T-24 hrs. Conclusions: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation. (Crit Care Med 2012; 40:2841-2849)

A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features

Background Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype. phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. Methods Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. Results The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype. phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. Conclusion A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

Executive functions of children born very preterm--deficit or delay?

This cross-sectional study examined the performance of children born very preterm and/or at very low birth weight (VPT/VLBW) and same-aged term-born controls in three core executive functions: inhibition, working memory, and shifting. Children were divided into two age groups according to the median (young, 8.00-9.86 years; old, 9.87-12.99 years). The aims of the study were to investigate whether (a) VPT/VLBW children of both age groups performed poorer than controls (deficit hypothesis) or caught up with increasing age (delay hypothesis) and (b) whether VPT/VLBW children displayed a similar pattern of performance increase in executive functions with advancing age compared with the controls. Fifty-six VPT/VLBW children born in the cohort of 1998-2003 and 41 healthy-term-born controls were recruited. All children completed tests of inhibition (Color-Word Interference Task, Delis-Kaplan Executive Function System (D-KEFS)), working memory (Digit Span Backwards, HAWIK-IV), and shifting (Trail Making Test, Number-Letter Sequencing, D-KEFS). Results revealed that young VPT/VLBW children performed significantly poorer than the young controls in inhibition, working memory, and shifting, whereas old VPT/VLBW children performed similar to the old controls across all three executive functions. Furthermore, the frequencies of impairment in inhibition, working memory and shifting were higher in the young VPT/VLBW group compared with the young control group, whereas frequencies of impairment were equal in the old groups. In both VPT/VLBW children and controls, the highest increase in executive performance across the ages of 8 to 12 years was observed in shifting, followed by working memory, and inhibition.

GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity

A heterozygous missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C), which was previously reported to have some GH antagonistic effect, was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) at the age of 6 years. His mother and grandfather were also carrying the same mutation, but did not differ in adult height from the other unaffected family members. Hormonal examination in all affected subjects revealed increased basal GH, low IGF-I concentrations, and subnormal IGF-I response in generation test leading to the diagnosis of partial GH insensitivity. However, GH receptor gene (GHR) sequencing demonstrated no abnormalities. As other family members carrying the GH-R77C form showed similar alterations at the hormonal level, but presented with normal final height, no GH therapy was given to the boy, but he was followed through his pubertal development which was delayed. At the age of 20 years he reached his final height, which was normal within his parental target height. Functional characterization of the GH-R77C, assessed through activation of Jak2/Stat5 pathway, revealed no differences in the bioactivity between wild-type-GH (wt-GH) and GH-R77C. Detailed structural analysis indicated that the structure of GH-R77C, in terms of disulfide bond formation, is almost identical to that of the wt-GH despite the introduced mutation (Cys77). Previous studies from our group demonstrated a reduced capability of GH-R77C to induce GHR/GH-binding protein (GHBP) gene transcription rate when compared with wt-GH. Therefore, reduced GHR/GHBP expression might well be the possible cause for the partial GH insensitivity found in our patients. In addition, this group of patients deserve further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity. This might be responsible for the delay of growth and pubertal development. Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory.

Diagnostic delay in Crohn's disease is associated with a complicated disease course and increased operation rate

OBJECTIVES The impact of diagnostic delay (a period from appearance of first symptoms to diagnosis) on the clinical course of Crohn's disease (CD) is unknown. We examined whether length of diagnostic delay affects disease outcomes. METHODS Data from the Swiss IBD cohort study were analyzed. Patients were recruited from university centers (68%), regional hospitals (14%), and private practices (18%). The frequencies of occurrence of bowel stenoses, internal fistulas, perianal fistulas, and CD-related surgery (intestinal and perianal) were analyzed. RESULTS A total of 905 CD patients (53.4% female, median age at diagnosis 26 (20-36) years) were stratified into four groups according to the quartiles of diagnostic delay (0-3, 4-9, 10-24, and ≥25 months, respectively). Median diagnostic delay was 9 (3-24) months. The frequency of immunomodulator and/or antitumor necrosis factor drug use did not differ among the four groups. The length of diagnostic delay was positively correlated with the occurrence of bowel stenosis (odds ratio (OR) 1.76, P=0.011 for delay of ≥25 months) and intestinal surgery (OR 1.76, P=0.014 for delay of 10-24 months and OR 2.03, P=0.003 for delay of ≥25 months). Disease duration was positively associated and non-ileal disease location was negatively associated with bowel stenosis (OR 1.07, P<0.001, and OR 0.41, P=0.005, respectively) and intestinal surgery (OR 1.14, P<0.001, and OR 0.23, P<0.001, respectively). CONCLUSIONS The length of diagnostic delay is correlated with an increased risk of bowel stenosis and CD-related intestinal surgery. Efforts should be undertaken to shorten the diagnostic delay.

Impact of delay in reducing carbon dioxide emissions

Recent downward revisions in the climate response to rising CO2 levels, and opportunities for reducing non-CO2 climate warming, have both been cited as evidence that the case for reducing CO2 emissions is less urgent than previously thought. Evaluating the impact of delay is complicated by the fact that CO2 emissions accumulate over time, so what happens after they peak is as relevant for long-term warming as the size and timing of the peak itself. Previous discussions have focused on how the rate of reduction required to meet any given temperature target rises asymptotically the later the emissions peak. Here we focus on a complementary question: how fast is peak CO2-induced warming increasing while mitigation is delayed, assuming no increase in rates of reduction after the emissions peak? We show that this peak-committed warming is increasing at the same rate as cumulative CO2 emissions, about 2% per year, much faster than observed warming, independent of the climate response.

Endovascular treatment for acute ischemic stroke patients: implications and interpretation of IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials: A report from the Working Group of International Congress of Interventional Neurology

OBJECTIVE The results of Interventional Management of Stroke (IMS) III, Magnetic Resonance and REcanalization of Stroke Clots Using Embolectomy (MR RESCUE), and SYNTHESIS EXPANSION trials are expected to affect the practice of endovascular treatment for acute ischemic stroke. The purpose of this report is to review the components of the designs and methods of these trials and to describe the influence of those components on the interpretation of trial results. METHODS A critical review of trial design and conduct of IMS III, MR RESCUE, and SYNTHESIS EXPANSION is performed with emphasis on patient selection, shortcomings in procedural aspects, and methodology of data ascertainment and analysis. The influence of each component is estimated based on published literature including multicenter clinical trials reporting on endovascular treatment for acute ischemic stroke and myocardial infarction. RESULTS We critically examined the time interval between symptom onset and treatment and rates of angiographic recanalization to differentiate between "endovascular treatment" and "parameter optimized endovascular treatment" as it relates to the IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials. All the three trials failed to effectively test "parameter optimized endovascular treatment" due to the delay between symptom onset and treatment and less than optimal rates of recanalization. In all the three trials, the magnitude of benefit with endovascular treatment required to reject the null hypothesis was larger than could be expected based on previous studies. The IMS III and SYNTHESIS EXPANSION trials demonstrated that rates of symptomatic intracerebral hemorrhages subsequent to treatment are similar between IV thrombolytics and endovascular treatment in matched acute ischemic stroke patients. The trials also indirectly validated the superiority/equivalence of IV thrombolytics (compared with endovascular treatment) in patients with minor neurological deficits and those without large vessel occlusion on computed tomographic/magnetic resonance angiography. CONCLUSIONS The results do not support a large magnitude benefit of endovascular treatment in subjects randomized in all the three trials. The possibility that benefits of a smaller magnitude exist in certain patient populations cannot be excluded. Large magnitude benefits can be expected with implementation of "parameter optimized endovascular treatment" in patients with ischemic stroke who are candidates for IV thrombolytics.

Delay effects in the response of low-grade gliomas to radiotherapy: a mathematical model and its therapeutical implications

Low-grade gliomas (LGGs) are a group of primary brain tumours usually encountered in young patient populations. These tumours represent a difficult challenge because many patients survive a decade or more and may be at a higher risk for treatment-related complications. Specifically, radiation therapy is known to have a relevant effect on survival but in many cases it can be deferred to avoid side effects while maintaining its beneficial effect. However, a subset of LGGs manifests more aggressive clinical behaviour and requires earlier intervention. Moreover, the effectiveness of radiotherapy depends on the tumour characteristics. Recently Pallud et al. (2012. Neuro-Oncology, 14: , 1-10) studied patients with LGGs treated with radiation therapy as a first-line therapy and obtained the counterintuitive result that tumours with a fast response to the therapy had a worse prognosis than those responding late. In this paper, we construct a mathematical model describing the basic facts of glioma progression and response to radiotherapy. The model provides also an explanation to the observations of Pallud et al. Using the model, we propose radiation fractionation schemes that might be therapeutically useful by helping to evaluate tumour malignancy while at the same time reducing the toxicity associated to the treatment.

Displaced supracondylar humeral fractures: influence of delay of surgery on the incidence of open reduction, complications and outcome.

BACKGROUND Closed reduction and pinning is the accepted treatment choice for dislocated supracondylar humeral fractures in children (SCHF). Rates of open reduction, complications and outcome are reported to be dependent on delay of surgery. We investigated whether delay of surgery had influence on the incidence of open reduction, complications and outcome of surgical treatment of SCHFs in the authors' institution. METHODS Three hundred and forty-one children with 343 supracondylar humeral fractures (Gartland II: 144; Gartland III: 199) who underwent surgery between 2000 and 2009 were retrospectively analysed. The group consisted of 194 males and 149 females. The average age was 6.3 years. Mean follow-up was 6.2 months. Time interval between trauma and surgical intervention was determined using our institutional database. Clinical and radiographical data were collected for each group. Influence of delay of treatment on rates of open reduction, complications and outcome was calculated using logistic regression analysis. Furthermore, patients were grouped into 4 groups of delay (<6 h, n = 166; 6-12 h, n = 95; 12-24 h, n = 68; >24 h, n = 14) and the aforementioned variables were compared among these groups. RESULTS The incidence of open procedures in 343 supracondylar humeral fractures was 2.6 %. Complication rates were similar to the literature (10.8 %) primarily consisting of transient neurological impairments (9.0 %) which all were fully reversible by conservative treatment. Poor outcome was seen in 1.7 % of the patients. Delay of surgical treatment had no influence on rates of open surgery (p = 0.662), complications (p = 0.365) or poor outcome (p = 0.942). CONCLUSIONS In this retrospective study delay of treatment of SCHF did not have significant influence on the incidence of open reduction, complications, and outcome. Therefore, in SCHF with sufficient blood perfusion and nerve function, elective treatment is reasonable to avoid surgical interventions in the middle of the night which are stressful and wearing both for patients and for surgeons. LEVEL OF EVIDENCE III (retrospective comparative study).

Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

BACKGROUND L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Controlled Cytokinin Production in Transgenic Tobacco Using a Copper-Inducible Promoter

The cytokinin group of plant hormones regulates aspects of plant growth and development, including the release of lateral buds from apical dominance and the delay of senescence. In this work the native promoter of a cytokinin synthase gene (ipt) was removed and replaced with a Cu-controllable promoter. Tobacco (Nicotiana tabacum L. cv tabacum) transformed with this Cu-inducible ipt gene (Cu-ipt) was morphologically identical to controls under noninductive conditions in almost all lines produced. However, three lines grew in an altered state, which is indicative of cytokinin overproduction and was confirmed by a full cytokinin analysis of one of these lines. The in vitro treatment of morphologically normal Cu-ipt transformants with Cu2+ resulted in delayed leaf senescence and an increase in cytokinin concentration in the one line analyzed. In vivo, inductive conditions resulted in a significant release of lateral buds from apical dominance. The morphological changes seen during these experiments may reflect the spatial aspect of control exerted by this gene expression system, namely expression from the root tissue only. These results confirmed that endogenous cytokinin concentrations in tobacco transformants can be temporally and spatially controlled by the induction of ipt gene expression through the Cu-controllable gene-expression system.

A comparative study: long and short term effect of a nutrition sensitive approach to delay the progression of HIV to AIDS among people living with HIV (PLWH) in Nigeria

Background: Malnutrition has a negative impact on optimal immune function, thus increasing susceptibility to morbidity and mortality among HIV positive patients. Evidence indicates that the prevalence of macro and micronutrient deficiencies (particularly magnesium, selenium, zinc, and vitamin C) has a negative impact on optimal immune function, through the progressive depletion of CD4 T-lymphocyte cells, which thereby increases susceptibility to morbidity and mortality among PLWH. Objective: To assess the short and long term effects of a nutrition sensitive intervention to delay the progression of human immune-deficiency virus (HIV) to AIDS among people living with HIV in Abuja, Nigeria. Methods: A randomized control trial was carried out on 400 PLWH (adult, male and female of different religious background) in Nigeria between January and December 2012. Out of these 400 participants, 100 were randomly selected for the pilot study, which took place over six months (January to June, 2012). The participants in the pilot study overlapped to form part of the scale-up participants (n 400) monitored from June to December 2012. The comparative effect of daily 354.92 kcal/d optimized meals consumed for six and twelve months was ascertained through the nutritional status and biochemical indices of the study participants (n=100 pilot interventions), who were and were not taking the intervention meal. The meal consisted of: Glycine max 50g (Soya bean); Pennisetum americanum 20g (Millet); Moringa oleifera 15g (Moringa); Daucus carota spp. sativa 15g (Carrot). Results: At the end of sixth month intervention, mean CD4 cell count (cell/mm3) for Pre-ART and ART Test groups increased by 6.31% and 12.12% respectively. Mean mid upper arm circumference (MUAC) for Pre-ART and ART Test groups increased by 2.72% and 2.52% within the same period (n 400). Comparatively, participants who overlapped from pilot to scale-up intervention (long term use, n 100) were assessed for 12 months. Mean CD4 cell count (cell/mm3) for Pre-ART and ART test groups increased by 2.21% and 12.14%. Mean MUAC for Pre-ART and ART test groups increased by 2.08% and 3.95% respectively. Moreover, student’s t-test analysis suggests a strong association between the intervention meal, MUAC, and CD4 count on long term use of optimized meal in the group of participants being treated with antiretroviral therapy (ART) (P<0.05). Conclusion: Although the achieved results take the form of specific technology, it suggests that a prolong consumption of the intervention meal will be suitable to sustain the gained improvements in the anthropometric and biochemical indices of PLWHIV in Nigeria.

Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR

We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor.

Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR

We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor.

Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the developing male Wistar(Han) rat II: chronic dosing causes developmental delay

We have investigated whether fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat, using chronically exposed rats to ensure continuous exposure of the fetus. 5-6 week old rats were exposed to control diet, or diet containing TCDD, to attain an average dose of 2.4, 8 and 46 ng TCDD kg-1 day-1 for twelve weeks, whereupon the rats were mated, and allowed to litter; rats were switched to control diet after parturition. Male offspring were allowed to develop until kills on PND70 (25 per group), or PND120 (all remaining animals). Offspring from the high dose group showed an increase in total litter loss, and the number of animals alive on post-natal day (PND) 4 in the high dose group was ~26% less than control. The high and medium dose offspring showed decreased weights at various ages. Balano-preputial separation was significantly delayed in all three dose groups, compared to control. There were no significant effects of maternal treatment when the offspring were subjected to a functional observational battery, or learning tests, with the exception that the high dose group showed a deficit in motor activity. 20 rats per group were mated to females, and there were no significant effects of maternal treatment on the fertility of these rats, nor on the F1 or F2 sex ratio. Sperm parameters at PND70 and 120 showed no significant effect of maternal treatment, with the exception that there was an increase in the proportion of abnormal sperm in the high dose group at PND70; this is associated with the developmental delay in puberty in this dose group. There were no remarkable findings of maternal treatment on organ weights, with the exception that testis weights were reduced by ~10% at PND70 (but not PND120), and although the experiment was sufficiently powered to detect small changes, ventral prostate weight was not reduced. There were no significant effects of maternal treatment upon histopathological comparison of high dose and control group organs. These data confirm that developmental exposure to TCDD shows no potent effect on adult sperm parameters or accessory sexual organs, but show that delay in BPS occurs after exposure to low doses of TCDD, and this is dependent upon whether TCDD is administered acutely or chronically.