Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group.

BACKGROUND: The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. AIM: The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. METHODS: Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). RESULTS: ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. CONCLUSIONS: The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach.

Are maternal hemodynamic indices markers of fetal growth restriction in pregnancies with a small-for-gestational-age fetus?

OBJECTIVE: Pregnancies complicated by fetal growth restriction (FGR) have a worse outcome than those with a small-for-gestational-age (SGA) fetus. There is increasing evidence of a maternal cardiovascular role in the pathophysiology of FGR. We aimed to compare maternal hemodynamic indices between pregnancies complicated by FGR and those delivering a SGA neonate, using a non-invasive device. METHODS: This was a prospective study of normotensive pregnancies complicated by FGR (defined as estimated fetal weight (EFW) < 3rd centile or Doppler evidence of impaired placental-fetal blood flow), those with a SGA fetus (defined as EFW < 10th centile) and control pregnancies with an appropriately grown fetus. Assessment of maternal hemodynamics (heart rate (HR), cardiac output (CO), mean arterial pressure (MAP), systemic vascular resistance (SVR) and stroke volume) was performed using a non-invasive device (USCOM-1A®). Uterine artery (UtA) pulsatility index (PI) was measured using transabdominal ultrasound. Hemodynamic variables that are affected by gestational age and maternal characteristics were corrected for using device-specific reference ranges. Comparison between groups was performed using the chi-square test or the Mann-Whitney U-test, as appropriate. RESULTS: A total of 102 FGR, 64 SGA and 401 control pregnancies, with a median gestational age of 36 weeks, were included in the analysis. Women with a pregnancy complicated by FGR and those with a SGA fetus were shorter and weighed less than did controls. Compared with controls, the FGR group had significantly lower median maternal HR (80 beats per min (bpm) vs 85 bpm; P = 0.001) and CO multiples of the median (MoM; 0.91 vs 0.98; P = 0.003), and higher median maternal MAP (90 mmHg vs 87 mmHg; P = 0.040), SVR MoM (1.2 vs 1.0; P < 0.001) and UtA-PI MoM (1.1 vs 0.96; P < 0.001), but there was no significant difference in stroke volume MoM (1.0 vs 0.98; P = 0.647). Compared with the SGA group, the FGR group had a significantly lower median HR (80 bpm vs 87 bpm; P = 0.022), and higher median maternal MAP (90 mmHg vs 85 mmHg; P = 0.025), SVR MoM (1.2 vs 1.0; P = 0.002) and UtA-PI MoM (1.1 vs 0.98; P = 0.005), but there was no significant difference in CO MoM (0.91 vs 0.96; P = 0.092) or stroke volume MoM (1.0 vs 1.0; P = 0.806). There were no significant differences in adjusted maternal hemodynamic indices between the SGA group and controls. CONCLUSION: Pregnancies complicated by FGR presented with impaired maternal hemodynamic function, as evidenced by lower HR and CO, as well as higher MAP, SVR and UtA resistance. Pregnancies delivering a SGA neonate, without evidence of FGR, had normal maternal hemodynamic function. Maternal hemodynamic indices may therefore be of value in distinguishing FGR from SGA pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Correlation between central and uterine hemodynamics in hypertensive disorders of pregnancy.

OBJECTIVE: Pregnancies affected by a hypertensive disorder (HDP) have increased uterine artery pulsatility index (UtA-PI) compared with that in healthy pregnancies. Women with HDP are also known to have lower cardiac output and increased systemic vascular resistance. The aim of this study was to investigate the relationship between central and uterine hemodynamics in HDP and uncomplicated pregnancy. METHODS: This was a prospective study of HDP and normotensive control singleton pregnancies presenting at a tertiary referral hospital between January 2012 and December 2017. Paired measurements of maternal hemodynamics, using a non-invasive device (USCOM-1A®), and UtA-PI were performed in the third trimester. HDP pregnancies were divided into preterm (onset < 37 weeks' gestation) and term (onset ≥ 37 weeks). Spearman's rank coefficient was used to assess the correlation between the central and uteroplacental hemodynamics. Regression analysis was performed to assess the association of UtA-PI with independent variables. RESULTS: We included 231 women with HDP (152 with preterm and 79 with term HDP) and 378 controls with normotensive pregnancy. Compared with controls, women with preterm HDP had significantly lower cardiac output (median (interquartile range (IQR)), 6.0 (5.1-7.2) vs 6.6 (5.8-7.5) L/min; P < 0.001) and significantly higher systemic vascular resistance (median (IQR), 1394 (1189-1670) vs 1063 (915-1222) dynes × s/cm5 ; P < 0.001) and UtA-PI (median (IQR), 1.0 (0.75-1.4) vs 0.67 (0.58-0.83); P < 0.001). Conversely, in women with term HDP, there were no significant differences in heart rate, cardiac output or UtA-PI compared with controls (all P > 0.05), while systemic vascular resistance was significantly higher (median (IQR), 1315 (1099-1527) vs 1063 (915-1222) dynes × s/cm5 ; P < 0.001). On multiple regression analysis, heart rate, mean arterial pressure and stroke volume were associated significantly with mean UtA-PI (all P < 0.001). CONCLUSIONS: Differences observed between HDP and normotensive pregnancies in third-trimester UtA resistance are mirrored in the central maternal hemodynamic parameters. Late pregnancy differences in the uteroplacental circulation in preterm and term HDP are an index of maternal cardiovascular function rather than being related to inadequate spiral artery remodeling and impaired placentation. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Maternal hemodynamics in normal pregnancy: reference ranges and role of maternal characteristics.

OBJECTIVES: The main aim of this study was to construct reference ranges of maternal central hemodynamic parameters during pregnancy. The second aim was to determine the maternal and pregnancy characteristics that influence these hemodynamic parameters. METHODS: This was a prospective cohort study of low-risk pregnant women attending for routine antenatal care at St George's Hospital, London, UK. Exclusion criteria included any medical disorder present at the time of study recruitment, or development of hypertension or intrauterine fetal growth restriction following study recruitment. Stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) were obtained using non-invasive cardiac output monitoring (USCOM-1A®). USCOM-1A utilizes a non-imaging probe in the suprasternal notch to obtain velocity-time integrals of transaortic blood flow at the left ventricular outflow tract. Once the distribution of the data with respect to gestational age had been determined, maternal characteristics were added to the model to test whether they provided a significant improvement in the prediction of the median value. RESULTS: The study included 627 women with a singleton pregnancy. The estimated median CO was constant for a maternal age above 32 years, but was around 0.5 L/min higher for women aged ≤ 25 years (P < 0.001). Maternal weight (P < 0.001) and height (P < 0.001) significantly affected CO values and there was a significant interaction (P = 0.002) between them. In women with a height of less than 1.60 m, there was no association between median CO and weight; however, in those with a height exceeding 1.60 m, an increase in weight was associated with an increase in CO. SV was primarily associated with height (P < 0.001), although some positive association with weight (P < 0.001) could also be observed within the normal body-mass-index range. Greater height (P < 0.001) was associated with lower median values of SVR, with an estimated difference of around 120 dynes × s/cm5 between 1.60 m and 1.80 m. Advancing maternal age was associated with higher median SVR, with an estimated difference of around 50 dynes × s/cm5 between 25 and 35 years. Smokers had a lower SVR by 73.5 (95% CI, 8.6-138.4) dynes × s/cm5 . CONCLUSION: Maternal hemodynamics are influenced significantly by maternal age, height and weight. We provide USCOM-1A-specific reference ranges and a calculator for SV, CO and SVR in uncomplicated pregnancies that correct for maternal age, height and weight. This should enable clinical application and comparison in both uncomplicated and pathological pregnancies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Impaired maternal hemodynamics in morbidly obese women: a case-control study.

OBJECTIVE: Maternal obesity is associated with significant pregnancy complications and is a risk factor for the development of hypertensive disorders of pregnancy as well as other adverse outcomes. There are few data regarding the hemodynamic aberrations observed in maternal obesity. The aim of this study was to investigate maternal hemodynamics in morbidly obese women. METHODS: This was a prospective, case-control study of morbidly obese women (body mass index (BMI) ≥ 40 kg/m2 ) and controls (BMI 20-29.9 kg/m2 ). The control population was matched for maternal age and gestational age. BMI was calculated based on maternal height and weight at the time of recruitment to the study, which occurred on the same day as the hemodynamic assessment. Pregnant women in the second or third trimester of pregnancy were included. Women who were found to be hypertensive at any time were excluded from the study. A USCOM-1A® device was used to assess hemodynamic parameters (heart rate, stroke volume (SV), cardiac output and systemic vascular resistance (SVR)). The parameters were corrected for body surface area (BSA) to provide the SV index (SVI), cardiac index (CI) and SVR index (SVRI). Mann-Whitney U-test was used to compare the medians of the hemodynamic variables between the two groups. RESULTS: In total, 23 morbidly obese women and 327 controls were included in the analysis. There was no difference in maternal (P = 0.506) or gestational (P = 0.693) age at recruitment between the groups. Mean arterial pressure was higher both at pregnancy booking (90 vs 80 mmHg, P < 0.001) and study recruitment (91 vs 85 mmHg, P < 0.001) in the obese group compared with the controls. Heart rate was higher in the obese group (P = 0.003), but there was no difference in SV (P = 0.271), cardiac output (P = 0.238) or SVR (P = 0.635). Following correction of these parameters for BSA, compared with the control group, SVI (34 vs 45 mL/m2 , P < 0.001) and CI (2.96 vs 3.64 L/min/m2 , P < 0.001) were significantly reduced in the obese group, whereas SVRI was significantly higher (2354 vs 1840 dynes × s/cm5 , P < 0.001). CONCLUSIONS: The findings of our study suggest that cardiac function is significantly altered in morbidly obese pregnant women. In order to make appropriate comparisons between individuals, it is imperative that hemodynamic parameters are indexed for BSA, as is standard practice in pediatric cardiology. The novel finding of reduced CI in morbidly obese pregnant women may explain the predisposition to pre-eclampsia and other adverse outcomes in this population and warrants further investigation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Outcome of first-trimester fetal abdominal cysts: cohort study and review of the literature.

OBJECTIVES: The aims of this study were to ascertain the outcome of fetuses with an abdominal cyst detected at 11-14 weeks' gestation in our unit and to undertake a review of cases reported in the literature. METHODS: This was a retrospective study that included all fetuses found to have an abdominal cyst on ultrasound examination at 11-14 weeks, identified over a 14-year period. Pregnancy management and outcome were ascertained from maternal and neonatal records. We also performed a review of the literature using a systematic search strategy, to identify the outcome of similar cases and propose a management algorithm. RESULTS: Fourteen cases were identified during the study period, of which four had associated abnormalities. Of the 10 isolated cases, the cyst had resolved at follow-up scan in eight (80.0%), one fetus died in utero at 15 weeks' gestation and the other case underwent surgery for a choledochal cyst 9 weeks after birth. An additional 19 cases were reported in the literature. In eight fetuses there were associated structural abnormalities, of which four had a diagnosis of anorectal malformation after birth. In two of these four, the cyst resolved in the second trimester. Of those cases with an isolated cyst (n = 11), the cyst resolved in seven (63.6%). The remainder were variably diagnosed as hepatic cyst, ileal duplication or choledochal cyst. CONCLUSION: Fetal abdominal cysts at 11-14 weeks' gestation are rare. They constitute an isolated finding in the majority of cases and are usually associated with a good perinatal outcome. In view of the reported association with anorectal and other gastrointestinal malformations, perinatal assessment is recommended, even if the cyst resolves during pregnancy.

Embryonic growth discordance and early fetal loss: the STORK multiple pregnancy cohort and systematic review.

STUDY QUESTION: Is there an association between discordance in embryonic growth and fetal loss at the time of the 11-14-week scan in twin pregnancies? SUMMARY ANSWER: Regardless of the chorionicity, crown rump length (CRL) discordance at 7(+0)-9(+6) weeks is predictive of subsequent single fetal demise in the first trimester. WHAT IS KNOWN ALREADY: Previous small studies have reported a variable association between discordance in embryonic growth and subsequent fetal loss. STUDY DESIGN, SIZE, DURATION: Retrospective study of all twin pregnancies of known chorionicity from a large regional cohort over a 10-year period. A total of 1356 twin pregnancies (288 monochorionic and 1068 dichorionic) were included in the study. PARTICIPANTS, SETTING, METHODS: Women presenting to the early pregnancy unit were included in the study. Logistic regression, ROC curve and Kaplan-Meier analyses were performed to evaluate the association between CRL discordance at 7(+0)-9(+6) weeks and spontaneous single fetal loss diagnosed at the 11-14-week scan. A systematic review was also performed using MEDLINE, EMBASE, Cinahl and the Cochrane Library in order to explore the relationship between early growth discordance and single fetal loss in twin pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE: There were 111 (8.2%) single fetal losses diagnosed at 11-14 weeks in this cohort. At multivariate analysis, CRL discordance percentile [odds ratio (OR) 1.20; 95% confidence interval (CI), 1.12-1.63, P < 0.0001] and CRL <5th centile of at least one twin (OR, 2.21; 95% CI 1.23-4.24, P = 0.023), but not chorionicity (P = 0.486) or maternal age (P = 0.283) was independently associated with the loss of one fetus at the 11-14-week scan. The predictive accuracy of CRL discordance for single fetal loss was high (AUC = 0.93; 95% CI = 0.91-0.94). A significant association was found between the increase in the degree of embryonic discordance and the likelihood of early fetal loss (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: Only a high-risk population was analysed. Therefore, the patients studied were not a representative sample from the population of women pregnant with twins. WIDER IMPLICATION OF THE FINDINGS: Twin pregnancies, in particular those resulting from assisted conception, are scanned frequently, particularly during the early stages of pregnancy. The findings of this study are likely to prove important in counselling parents about the short-term outcome of the pregnancy when an embryonic discordance is present. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflicts of interest to declare.

Description of Lyme disease-like syndrome in Brazil. Is it a new tick borne disease or Lyme disease variation?

An emerging clinical entity that reproduces clinical manifestations similar to those observed in Lyme disease (LD) has been recently under discussion in Brazil. Due to etiological and laboratory particularities it is named LD-like syndrome or LD imitator syndrome. The condition is considered to be a zoonosis transmitted by ticks of the genus Amblyomma, possibly caused by interaction of multiple fastidious microorganisms originating a protean clinical picture, including neurological, osteoarticular and erythema migrans-like lesions. When peripheral blood of patients with LD-like syndrome is viewed under a dark-field microscope, mobile uncultivable spirochete-like bacteria are observed. PCR carried out with specific or conservative primers to recognize Borrelia burgdorferi sensu stricto or the genus Borrelia has been negative in ticks and in biological samples. Two different procedures, respectively involving hematoxylin and eosin staining of cerebrospinal fluid and electron microscopy analysis of blood, have revealed spirochetes not belonging to the genera Borrelia, Leptospira or Treponema. Surprisingly, co-infection with microorganisms resembling Mycoplasma and Chlamydia was observed on one occasion by electron microscopy analysis. We discuss here the possible existence of a new tick-borne disease in Brazil imitating LD, except for a higher frequency of recurrence episodes observed along prolonged clinical follow-up.

Dissection of Genetic Factors underlying Wheat Kernel Shape and Size in an Elite × Nonadapted Cross using a High Density SNP Linkage Map.

Wheat kernel shape and size has been under selection since early domestication. Kernel morphology is a major consideration in wheat breeding, as it impacts grain yield and quality. A population of 160 recombinant inbred lines (RIL), developed using an elite (ND 705) and a nonadapted genotype (PI 414566), was extensively phenotyped in replicated field trials and genotyped using Infinium iSelect 90K assay to gain insight into the genetic architecture of kernel shape and size. A high density genetic map consisting of 10,172 single nucleotide polymorphism (SNP) markers, with an average marker density of 0.39 cM/marker, identified a total of 29 genomic regions associated with six grain shape and size traits; ∼80% of these regions were associated with multiple traits. The analyses showed that kernel length (KL) and width (KW) are genetically independent, while a large number (∼59%) of the quantitative trait loci (QTL) for kernel shape traits were in common with genomic regions associated with kernel size traits. The most significant QTL was identified on chromosome 4B, and could be an ortholog of major rice grain size and shape gene or . Major and stable loci also were identified on the homeologous regions of Group 5 chromosomes, and in the regions of (6A) and (7A) genes. Both parental genotypes contributed equivalent positive QTL alleles, suggesting that the nonadapted germplasm has a great potential for enhancing the gene pool for grain shape and size. This study provides new knowledge on the genetic dissection of kernel morphology, with a much higher resolution, which may aid further improvement in wheat yield and quality using genomic tools.

Statin monotherapy attenuates renal injury in a salt-sensitive hypertension model of renal disease.

BACKGROUND: Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27. METHODS: Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-beta1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA). RESULTS: SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 +/- 7.3 vs. 84.4 +/- 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-beta did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 +/- 6.6 vs. 50.2 +/- 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 +/- 0.40 vs. 4.07 +/- 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV. CONCLUSION: SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.

Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial.

BACKGROUND: Critically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness. METHODS: A single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation >48 hours and Simplified Acute Physiology Score II>32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered. RESULTS: Melatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation. CONCLUSION: Long-term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.

Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations.

The purpose of this study was to investigate the association among matrix metalloproteinases (gelatinases A and B, stromelysin-3 (ST3) and matrilysin) mRNAs expressed in primary breast carcinomas and standard prognostic parameters and clinical outcome. mRNA levels were determined by Northern analysis in samples of 81 breast cancer patients (median follow-up, 40 months) and 27 samples of uninvolved adjacent breast tissue. Proteases were expressed by the majority of the tumors and normal breast tissues examined. ST3, gelatinase A and matrilysin mRNAs were more often expressed at high levels in carcinomatous than in normal breast tissues. Differences in the distribution of gelatinase B mRNA were not found. However, paired normal tissues generally produced weaker signals when compared to matched tumor samples. Univariate analysis showed no significant association of gelatinase A and matrilysin mRNAs with the classical prognostic markers (age, menopausal status, stage, size, nodal status, vascular infiltrate, necrosis, steroid receptors, metastasis and survival). Overexpression of ST3 was more frequently found in tumors of post-menopausal women (P < 0.022). Elevated expression of gel B mRNA was associated with the presence of vascular infiltrate (P < 0.026), necrosis (P < 0.039), PR negative tumors (P < 0.014) and inversely correlated to the number of survivors (P < 0.021). Multivariate analysis including 68 patients for whom all information was available indicated that neither stromelysin correlated significantly with pathological, clinical or biochemical features. High levels of gelatinase A and B mRNAs were inversely associated with the number of survivors. Our findings suggest that measurements of gelatinase A and B mRNAs expression in breast carcinoma may help to identify patients with an aggressive form of the disease.

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study.

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.

Prognostic significance of the combined expression of matrix metalloproteinase-9, urokinase type plasminogen activator and its receptor in breast cancer as measured by Northern blot analysis.

Using Northern blot analysis we have measured the co-expression of the matrix metalloprotease MMP-9, plasminogen activator urokinase type (uPA) and its receptor (uPAR) mRNAs in 81 biopsies of breast carcinomas with the objective of analyzing the impact of these factors on the overall survival probability of the patients (median follow-up time: 4 years). Individual mRNA levels of either uPA or uPAR showed parallel variations with MMP-9 mRNA, suggesting a coordinate transcription of these markers. When median values were used as cutoff points to discriminate between high and low factor expression, no association was found with patient outcome and MMP-9 or uPA mRNA distribution. However, increased uPAR mRNA levels were associated with poor prognosis (p = 0.01). The combination of MMP-9 and uPAR mRNA measurements has not enhanced prognostic information compared to information supplied by the receptor alone (p = 0.01). The combination of MMP-9 and high levels of uPA mRNA led to a significant association with poor outcome (p = 0.03). Multivariate analysis supported the notion that increased uPAR mRNA production in primary breast cancer may be a predictor of overall survival.

Cardio-toxicity of Daunomycin and Adriamycin.

Our aim was to check the possibility of modifying the cardio-toxicity of Daunomycin and Adriamycin on guinea pig atria in vitro, through a reduction of calcium concentration in the medium. In a first series of tests, left and right atria still beating were put in a bath containing Tyrode solution. In order to test the influence of hypocalcic conditions on the negative inotropic effects of the two drugs. Tyrode solution contained either the usual amount of calcium or only 50% of it. In a second series of experiments isolated tissues were electrically stimulated in Krebs-bicarbonate solution. In order to avoid the spontaneous activity of the preparations, only isolated left atria were used. Again the medium contained either the normal quantity of calcium or only 50%. The reduction of calcium concentration in the medium results in a statistically significant potentiation of the negative inotropic activity of the two drugs.

A native whole blood test for the evaluation of blood-surface interaction: determination of thromboxane production.

The method developed to evaluate the hemocompatibility of artificial materials involves the determination of thromboxane production during the clotting of rabbit blood, in test tubes of different materials. The concentration of serum TXB2 obtained after incubation of whole blood in glass test tubes, for 40 min at 37 degrees C, averaged 416.8 +/- 23.3 ng/ml (mean +/- SE). Polymethylpentene, recognised as having a relatively poor blood compatibility, elicited 309.5 +/- 17.2 ng/ml of serum TXB2, while silicone and Avcothane, considered of better hemocompatibility, showed thromboxane levels of 276.2 +/- 28.2 and 222.9 +/- 31.5 ng/ml, respectively. These values validate the usefulness of the proposed method as a preliminary in vitro screening test of artificial materials intended for biomedical application.

EPR characterization of cellulose triacetate fibers used for enzyme immobilization.

EPR studies of a nitroxide spin label and of the nitroxide spin-labeled albumin entrapped in cellulose triacetate fibers were carried out.The EPR spectra have shown that within the fiber only two phases are present: a liquid one of medium viscosity trapped inside microcavities, and a polymeric one surrounding them.After entrapment, spin-labeled albumin is distributed mainly in the liquid phase, though a not negligible amount of it remains within the polymeric matrix.The EPR studies have shown that, after the standard procedure of drying, the albumin is almost completely precipitated, but about 85% of it returns to solution when the fiber is again placed in the solution.The behavior of the albumin dissolved inside the microcavities toward denaturating agents and pH change, and that of the free albumin in solution is similar; the minor differences noticed indicate a second-order interaction between the fiber and the protein.

Myopia evolution in pre-school children after full optical correction.

The optical correction of myopia is a controversial procedure in immature human eyes due to the limited knowledge of the mechanisms regulating emmetropization and to the lack of controlled clinical trials. The authors reviewed retrospectively the records of 42 myopic children (16 males and 26 females, mean age 34 months, range 17-54) for whom full optical correction was prescribed and refraction evaluated with cycloplegic autorefractometry. The mean Spherical Equivalent (SphEq) at the diagnosis (To) was 6.062±3.67 diopters. Eighteen patients had isomyopic (±1D difference SphEq), 15 anisomyopic and 9 antimetropic eyes. No differences were found at To in the mean sphere, cylinder, SphEq and age of first correction between males and females. Follow-up was 42±17 and 47±23 months respectively for each sex (T1). Compliance with spectacles was generally good. At T1, the mean SphEq was significantly reduced in the whole group (-5.32±3.39, P<0.001). However, analyzing the sexes separately, it was found that only spherical progression was halted in males, whereas females showed a significant reduction both in sphere (p<0.001) and in cylinder (p<0.001). Final visual acuity was 0.86±0.18 and 0.86±0.26 (p: n.s.). The authors conclude that full optical correction did not exacerbate myopia progression in infants. Females showed a higher plasticity to the emmetropization process. Myopia increased mostly in undercorrected patients, and decreased with spectacles in 61% of isomyopic, 73% of anisomyopic and 77% of antimetropic patients. These observations support the hypothesis that visual input can modulate eye growth, calling for an early correction strategy for controlling myopia in infants.

Daily monitoring of biomarkers of sepsis in complicated long-term ICU-patients: can it support treatment decisions?

BACKGROUND: Diagnosis/grading of infection and the systemic response to infection may be difficult on admission to the intensive care unit, but it is even more complicated for severely ill patients with long intensive care stays. The ACCP-SCCM criteria are difficult to apply for such patients, and objective, validated biomarkers would be of great use in this setting. METHODS: Long-term (>6 days) critically ill patients in the general ICU of University Hospital were prospectively enrolled in the study. All patients were assessed daily by the attending physician using the ACCP-SCCM classification. C-reactive protein (CRP, mg/dL), procalcitonin (PCT, ng/mL), and interleukin-6 (IL-6, pg/mL) of daily stored sera were measured after each patient's discharge. After discharge, an independent, overall clinical evaluation and an a posteriori ACCP-SCCM classification were chosen as the reference standard for all comparisons. The assessor was aware of the patient's clinical course but was blinded to levels of biomarkers. RESULTS: We studied clinical variables and biomarkers of 26 patients over a total of 592 patient days. The day-by-day ACCP-SCCM classification of the attending physician overestimated the severity of the inflammatory response to infection. The diagnostic discriminative ability of severe-sepsis/septic-shock for PCT was high (ROC area 0.952 [0.931-0.973]) and had a best threshold value of 1.58 (83.7% sensitivity, 94.6 % specificity). IL-6 had better discriminative ability than CRP, but both were worse than PCT. CONCLUSION: PCT > 0.43 ng/mL could add to the clinical propensity for sepsis vs. SIRS not related to infection. Values higher than 1.58 ng/mL may support the bedside clinical diagnosis of severe-sepsis. PCT between 0.5 and 1.0 suggest tight daily monitoring of clinical conditions and re-evaluation of PCT.