The matrilin-3 VWA1 domain modulates interleukin-6 release from primary human chondrocytes.

OBJECTIVE: We previously demonstrated the ability of matrilin-3 to modulate the gene expression profile of primary human chondrocytes (PHCs) toward a state favoring cartilage catabolism. The structure within matrilin-3 responsible for the induction of these catabolic genes is unknown. Here, we investigated the potential of matrilin-3 (MATN3) and truncated matrilin-3 proteins, in both monomeric and oligomeric form, to stimulate interleukin (IL)-6 release in PHCs. METHODS: We expressed full-length matrilin-3 oligomers, matrilin-3 von Willebrand factor A (VWA) domain oligomers, matrilin-3 four epidermal growth factor (EGF) domain oligomers, matrilin-3 monomers without oligomerization domains, matrilin-3 VWA domain monomers, and matrilin-3 4EGF monomers. We then incubated PHCs in the absence or presence of full-length matrilin-3 or one of the truncated matrilin-3 proteins and finally determined the release of IL-6 in cell-culture supernatants. RESULTS: The addition of full-length matrilin-3 oligomers, matrilin-3 VWA domain oligomers, and, less pronounced, matrilin-3 monomers without oligomerization domains, and matrilin-3 4EGF-oligomers to the cell-culture medium led to a significant induction of IL-6 in PHCs. DISCUSSION: Based on recombinant expression of different matrilin-3 domains in both monomeric and oligomeric form, this work demonstrated that the VWA1 domain of matrilin-3 is primarily responsible for the induction of IL-6 release and that the oligomerization of the VWA1 domain markedly promotes its activity.

Endoscopic closure of gastrointestinal perforations and fistulas using the Ovesco Over-The-Scope Clip system at a tertiary care hospital center. / Cierre endoscópico de perforaciones y fístulas del tracto digestivo mediante el sistema «Over-the scope clip¼ (Ovesco), en un centro terciario.

INTRODUCTION AND AIM: Enteric perforations and fistulas are difficult to manage due to comorbidities, poor nutritional status, and anatomic challenges related to multiple interventions in those patients. The use of endoscopic methods as a nonsurgical approach is increasing. The aim of the present study was to describe the clinical experience with the use of the Ovesco Over-The-Scope Clip system in the closure of perforations, fistulas, and other indications in the digestive tract at a tertiary care hospital center. MATERIALS AND METHODS: A case series was carried out on patients that underwent lesion closure with the Ovesco clip, within the time frame of January 2015 to December 2017. RESULTS: The Ovesco clip was used for closure in 14 patients ranging in age from 21-90 years, with different indications: iatrogenic perforations; anastomotic leaks and fistulas; tracheoesophageal fistulas; and esophagogastric perforation. Technical success was achieved in 100% of the patients and clinical success in 78.57%. No complications were reported. CONCLUSIONS: The Ovesco Over-The-Scope Clip system is a safe and effective method for managing gastrointestinal acute perforations and fistulas.

Mortality of full-term infants during the first month of life in a tertiary care hospital.

OBJECTIVE: The neonatal mortality rate is disproportionately influenced by preterm infants and does not reflect the rate in full-term infants. Our objectives were to estimate the full-term neonatal mortality rate and to identify causes of death in full-term infants during the first month of life. STUDY DESIGN: A retrospective study of full-term infant deaths during a 6-year period from 2000 to 2005, in a tertiary medical center. RESULT: During the study period there were 44,703 full-term births and 31 deaths, representing a mortality rate of 0.69 per 1,000 live births. The main cause of death was congenital anomalies (64.5%), specifically cardiac anomalies. Other causes were chromosomal anomalies or syndromes (12.9%), labor complications (12.9%), infections (3.2%), congenital diseases (3.2%) and metabolic disorders (3.2%). CONCLUSION: The mortality rate of full-term infants may be lower than previous estimates. Efforts aimed at decreasing mortality among full-term infants should focus on prenatal diagnosis.

Bronchopulmonary dysplasia in very low birth weight infants is associated with prolonged hospital stay.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with prolonged hospital length of stay (LOS) and delayed discharge home. OBJECTIVES: To evaluate the association between BPD and LOS and to assess the contribution of concomitant major morbidities on LOS among infants with BPD. STUDY DESIGN: A population-based observational study of very low birth weight (VLBW) infants born from 1995 through 2003. Multivariate analyses, adjusted for perinatal variables, assessed the association between BPD and concomitant morbidities on LOS. RESULTS: Of 10 134 survivors, 1926 (19.0%) had BPD. The adjusted LOS for infants with and without BPD was 84.1 days (95% CI, 82.8, 85.6) and 58.1 days (95% CI, 57.2, 59.0), respectively. Addition of a single concomitant morbidity increased mean LOS by 4 to 13 days. CONCLUSIONS: BPD is a major cause of increased length of hospitalization among VLBW infants. Preventive or therapeutic modalities are required to reduce the significant burden of this condition.

Risk factors associated with post-hemorrhagic hydrocephalus among very low birth weight infants of 24-28 weeks gestation.

OBJECTIVE: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH). STUDY DESIGN: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH. RESULTS: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17). CONCLUSIONS: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.

Do hyperoxaemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia?

BACKGROUND: Episodes of hyperoxaemia and hypocapnia, which may contribute to brain injury, occur unintentionally in severely asphyxiated neonates in the first postnatal hours. OBJECTIVE: To determine whether hyperoxaemia and/or hypocapnia during the first 2 hours of life add to the risk of brain injury after intrapartum asphyxia. METHODS: Retrospective cohort study in term infants with post-asphyxial hypoxic ischaemic encephalopathy (HIE) born between 1985 and 1995. Severe and moderate hyperoxaemia were defined as Pao(2) >26.6 and Pao(2) >13.3 kPa (200 and 100 mm Hg). Severe and moderate hypocapnia were defined as Paco(2) <2.6 and Paco(2) <3.3 kPa (20 and 25 mm Hg). Adverse outcome ascertained by age 24 months was defined as death, severe cerebral palsy, or any cerebral palsy with blindness, deafness, or developmental delay. With outcome as the dependent variable, multivariate analyses were performed including hyperoxaemic and hypocapnic variables, and factors adjusted for initial disease severity. RESULTS: Of 244 infants, 218 had known outcomes, 127 of which were adverse (64 deaths, 63 neurodevelopmental deficits). Multivariate analyses showed an association between adverse outcome and episodes of severe hyperoxaemia (odds ratio (OR) 3.85, 95% confidence interval (CI) 1.67 to 8.88, p = 0.002), and severe hypocapnia (OR 2.34, 95% CI 1.02 to 5.37, p = 0.044). The risk of adverse outcome was highest in infants who had both severe hyperoxaemia and severe hypocapnia (OR 4.56, 95% CI 1.4 to 14.9, p = 0.012). CONCLUSIONS: Severe hyperoxaemia and severe hypocapnia were associated with adverse outcome in infants with post-asphyxial HIE. During the first hours of life, oxygen supplementation and ventilation should be rigorously controlled.

Adams-Oliver syndrome: autosomal recessive inheritance and new phenotypic-anthropometric findings.

We describe a new family with Adams-Oliver syndrome. One sib had scalp aplasia cutis congenita (SACC) and cutis marmorata and a second sib had SACC, cutis marmorata, and terminal lower limb defects. In both the findings were associated with oligohydramnios. The pedigree suggests autosomal recessive inheritance. New phenotypic-anthropometric findings in one infant were upper limb micromelia and brachypodia.

Normal pulmonary function in a monoamniotic twin discordant for bilateral renal agenesis: report and review.

Renal agenesis and obstructive urinary tract anomalies causing oligohydramnios usually result in pulmonary hypoplasia. We report on the first female monoamniotic twin born with a combination of bilateral renal agenesis, agenesis of the urinary collecting system, absent external genitalia, anal atresia and single umbilical artery, compatible with VATER association but with normal pulmonary function. The infant had none of the manifestations of Potter sequence, in particular the facial changes and pulmonary hypoplasia typically associated with bilateral renal a/dysgenesis. The monoamniotic cotwin had normal renal function, such that sufficient amniotic fluid volume was maintained. This patient emphasizes the importance of adequate amniotic fluid volume for normal pulmonary development. The possible underestimation of genital malformations in the VATER association should be considered. Also noteworthy is the rare absence of external genitalia.

In vivo hamster skeletal muscle preparation: morphine sensitive - naloxone insensitive.

The hamster cheek pouch retractor muscle preparation has been evaluated as an assay model for morphine and the opiate antagonist, naloxone. The preparation is in vivo and stimulation of the muscle is reflex. The higher the concentration of morphine injected into the pouch the greater was the average percent reduction in contractile force. Unilateral injections of morphine did not affect the contralateral muscle and so action of the drug was judged to be peripheral and local. The results with naloxone suggested that the opiate receptors in this preparation were relatively insensitive to the drug. The model has potential as an in vivo assay system for testing opiates, opiate agonists and antagonists. It may also prove to be valuable in studying tolerance to opiates and the withdrawal syndrome, as well as serving as a model for pain modulation studies.

A new in vivo method for quantitatively evaluating local anesthetics.

A method utilizing the reflex contraction of the retractor muscle of the hamster cheek pouch was developed to evaluate onset and duration of blockade produced by a local anesthetic agent infiltrated into or absorbed through the pouch epithelium. It provides a quantitative measure of reflex tension developed by the muscle as a function of afferent nerve conductivity in the pouch. The method is based upon the fact that when the pouch is everted activation of the retractor muscle results in the pouch being pulled toward the oral cavity. The method was validated by comparing the results with those obtained with other animal models and clinical trials. Ketocaine, an experimental drug, was evaluated for its efficacy as a local anesthetic when administered topically. In its present formulation the long latency of onset of blockade renders it impractical for clinical use.

Risk factors associated with candidaemia in the neonatal intensive care unit: a case-control study.

The incidence of candidaemia is steadily increasing in neonatal intensive care units (NICUs). Several neonatal risk factors for candidaemia have been identified, however, the number of cases in controlled studies is small and knowledge concerning maternal and perinatal risk factors is limited. The present study attempted to identify modifiable, independent maternal, perinatal and neonatal risk factors for candidaemia using a retrospective case-control study in the NICU of a tertiary-care paediatric medical centre. The study group consisted of 56 neonates admitted to the NICU between 1996 and 2000 who acquired candidaemia. The control group comprised the first infant admitted immediately after each study infant matched for gestational age (+/-10 days) and birthweight (+/-200 g). Potential maternal, perinatal and neonatal risk factors were compared between the groups using statistical methods and analysed by univariate and multivariate stepwise logistic regression models. The independent risk factors found to be significantly associated with increased risk of candidaemia were duration of ventilation and presence of bacteraemia before candidaemia. Maternal steroids had a significant protective effect. The positive predictive value using these three parameters was 78.38%. Maximizing in-utero steroid treatment in high-risk pregnancies, minimizing the days of mechanical ventilation and investment of efforts in prevention of bacteraemia may help to reduce the incidence of candidaemia in the NICU.

Influence of hormonal contraceptives on microbial flora of gingival sulcus.

To determine a possible influence of two different hormonal contraceptives on bacterial microflora of gingival sulcus, subgingival plaque samples of 29 healthy women aged between 20 and 32 years were investigated bacteriologically before subjects took a contraceptive and 10 and 20 days after subjects started the medication. In 14 women, and oral contraceptive containing 0.02 mg ethinyl estradiol and 0.15 mg desogestrel (preparation A) was used, and 15 women took a contraceptive containing 0.03 mg ethinyl estradiol and 2.00 mg dienogest (preparation B) daily over 21 days. There were no changes in clinical parameters of the teeth investigated during 3 weeks of the study. The periodontopathogenic bacteria Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were never detected throughout the study. On the other hand, the periodontopathogenic species Prevotella intermedia was found in plaque samples of 22 women. The content of this microorganism showed only a little change between the pretreatment period and plaque sampling after 10 days of contraceptive treatment, but a striking increase occurred after 20 days of contraceptive treatment, especially in the preparation A group. In this respect, there was a significant difference between preparations A and B.

PIP: Several studies have suggested an association between sex hormones and chronic inflammatory periodontal disease. This study investigated the impact of two oral contraceptives (OCs) on bacterial microflora of gingival sulcus samples obtained from 29 women 20-32 years of age recruited from Jena (Germany) University Women's Hospital. Study participants were randomly assigned to receive an OC containing either 0.02 mg of ethinyl estradiol and 0.15 mg of desogestrel (n = 14) or 0.03 mg of ethinyl estradiol and 2.00 mg of dienogest (n = 15). Subgingival plaque samples were obtained before and 10 and 20 days after the initiation of OC use. No changes in clinical parameters of the upper incisors (i.e., bleeding on probing, pocket depth, plaque) occurred in either study group during 21 days of OC use. Although Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were not detected, 22 plaque samples showed evidence of the periodontopathogenic bacteria Prevotella intermedia. The mean cultivable content of this microorganism increased significantly in users of the OC containing desogestrel from 1.2% at day 10 of OC use to 10.0% at day 20, but decreased slightly in women assigned to the OC containing dienogest and a higher dose of ethinyl estradiol. Good oral hygiene is essential in pregnancy and during OC use to compensate for hormonal influences and prevent gingivitis.

Effects of two oral contraceptives on plasma levels of insulin-like growth factor I (IGF-I) and growth hormone (hGH).

UNLABELLED: In 18 healthy women, the effect of two oral contraceptives (OCs) on insulin-like growth factor (IGF-I) and its binding protein-3 (IGFBP-3) and growth hormone (hGH) plasma level were studied before and after intake of either of two OC formulations over 21 days, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). There was a reduction of the mean IGF-I concentration of 30% (p = 0.008) in the women receiving dienogest-containing pills and 12% (p = 0.006) in women taking the levonogestrel-containing preparation. This difference between drug groups was statistically significant (p = 0.002). A correlation between the control values and the basal-treatment difference (r = 0.945; p = 0.000) was observed only in women of group A. Between basal and treatment cycles the mean plasma levels of hGH remained unchanged in both groups tested, but the 23.5-h integrated mean hGH plasma concentrations (AUC(0-23.5h)) were significantly elevated by 36% (p = 0.016) in comparison to basal values before treatment only in women receiving the levonorgestrel-containing pills. Also, in the women who received the dienogest-containing preparation, the changes of integrated mean plasma level were inversely associated with the control values (r = -0.723; p = 0.025). Neither in group A nor in group B was the mean plasma level of IGFB-3 changed. IN CONCLUSION: the results of the present analysis indicate that hormonal contraceptives can modulate the GH and IGF-I-axis in the reproductive age. Probably the androgenic progestogen levonorgestrel (0.125 mg/day) opposes the estrogen-induced action. In the women who took the dienogest-containing formulations (anti-androgenic progestogen-group A), the extent of individual changes (hGh and IGF-I) depends on the basal level prior to pill intake. Further studies, especially of long-term intake of OCs, are necessary to confirm these results and to assess the practical relevance for possible effects on connective tissue and bone.

The influence of Microgynon and Diane-35, two sub-fifty ovulation inhibitors, on voice function in women.

The early days of oral contraceptives showed some evidence that these medications may have caused undesirable side effects on the voice, mainly in terms of virilization. In a random study carried out at the university hospitals of Jena and Berlin (Charité), two more recent drugs were tested in this regard, one containing cyproterone acetate (Diane-35) and the other one levonorgestrel (Microgynon), both from Schering. Ninety-one patients took part in extensive clinical and instrumental phoniatric investigations of voice function over a period of one year. No significant side effects on the voice could be proven for the two preparations. Gynecological and clinical effects of both Diane-35 and Microgynon were similar during the one-year study period. Women taking Diane-35 had less intracyclic bleedings and amenorrhea. Also, acne was more favorably influenced by Diane-35.

PIP: The voice apparatus and skin are target organs for androgens, with the voice becoming deeper under the influence of androgens. There is some evidence that first-generation oral contraceptives may have affected users' voices. The authors report their findings of an evaluation of the effects of Microgynon and Diane-35, recent oral contraceptives manufactured by Schering, upon the voices of 91 female patients. Microgynon contains cyproterone acetate, while Diane-35 contains levonorgestrel. Extensive clinical and instrumental phoniatric investigations of voice function were conducted over a one-year period. Neither drug was found to have a significant side effect upon the voice, while gynecological and clinical effects of the drugs were similar during the study period. Women taking Diane-35 had less intracyclic bleeding and amenorrhea, and realized a comparatively favorable effect of the drug upon acne.

Can grapefruit juice influence ethinylestradiol bioavailability?

The effects of grapefruit juice on the bioavailability of 17 alpha-ethinylestradiol (EE2) after a single oral administration of 50 micrograms EE2 have been investigated. The pharmacokinetics of EE2 were studied in an open, randomized, cross-over study in which 13 healthy volunteers were administered the drug with herbal tea or grapefruit juice (naringin, 887 mg/ml). In contrast to herbal tea, grapefruit juice increased the peak plasma concentration (Cmax) significantly to 137% (mean; range 64% to 214%, p = 0.0088) and increased the area under plasma concentration-time curve from 0 to 8 hours (AUC0-8) to 128% (mean; range 81% to 180%, p = 0.0186). This study shows that grapefruit juice increases the bioavailable amount of EE2. A possible explanation may be that grapefruit juice inhibits the metabolic degradation of EE2. Whether the increased bioavailability of EE2 following grapefruit juice administration is of clinical importance should be investigated in long-term studies.

Prognostic value of EEG in neonatal bacterial meningitis.

The contribution of electroencephalogram (EEG) findings early in the course of neonatal bacterial meningitis to the prediction of severe adverse outcome was assessed in a retrospective cohort study. Infants had known outcomes to 1 year of age and an EEG performed during the first week of illness. EEGs were subclassified as follows: overall EEG description, background activity, presence of positive rolandic sharp waves, presence of seizure activity, and presence of focal abnormal activity. EEG patterns predictive of severe adverse outcome were identified by univariate and multivariate analyses. Of 101 infants admitted with bacterial meningitis, 37 had an EEG performed. Of the 37 infants, 21 had adverse outcomes; nine infants died, and 12 infants had moderate or severe disability. EEG background activity and overall EEG description were identified as predictors of adverse outcome; multivariate analysis indicated that the latter was a stronger predictor (sensitivity 88%, specificity 90%). Infants with normal or mildly abnormal EEGs had good outcomes whereas those with moderate to markedly abnormal EEGs died or survived with adverse outcome. The accuracy of predictions increased when EEGs were repeated. In a high-risk population of infants with bacterial meningitis, moderate-to-markedly abnormal EEG reliably predicts adverse outcome.