Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI.

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.

Anatomical variations of median nerve formation, distribution and possible communication with other nerves in preserved human cadavers.

Formation, distribution and possible communication of the median nerve are essential to know in treatment and surgeries of various conditions of injuries e.g. repair or reconstruction of the median nerve post traumatic accident. In the present study, 44 upper limbs were dissected. Root forming the median nerve, the median nerve in relation with the axillary artery and communication of the median nerve with other nerves were noted.

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats.

Hippocampal theta oscillations are linked to various processes, including locomotion, learning and memory, and defense and affect. The lateral septum (LS) has been implicated in the generation of the hippocampal theta rhythm, but its precise role in this process is not well understood. Here, we investigated the effects of direct pharmacological inhibition or disinhibition of the dorsal LS (dLS) on the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in urethane-anesthetized rats. We found that bilateral infusions of the GABAA receptor agonist muscimol into the dLS significantly increased theta frequency. Strikingly, intra-dLS infusions of the GABAA receptor antagonist GABAzine largely abolished reticularly elicited theta activity. We also locally injected these same compounds into the medial septum (MS) to test for neuroanatomical specificity. In contrast to the effects seen in the dLS, intra-MS infusions of muscimol had no effect on theta frequency, whereas intra-MS infusions of GABAzine increased theta frequency. Given the hypothesized role of hippocampal theta in behavioral defense, we also examined the effects of intra-dLS application of muscimol in two models of anxiety, the elevated plus maze and the novelty-induced suppression of feeding paradigm; both tests revealed clear, anxiolytic-like effects following muscimol infusions. The fact that dLS-muscimol increased theta frequency while also reducing anxiety-like behaviors challenges the influential theta suppression model of anxiolysis, which predicts a slowing of theta with anxiolytic compounds. More importantly, the experiments reveal a novel role of the LS, especially its dorsal aspects, as an important gating mechanism for the expression of theta oscillations in the rodent hippocampus.

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats.

Hippocampal theta activity is linked to various processes, including locomotion, learning and memory, and defense and affect (i.e., fear and anxiety). Interestingly, all classes of clinically effective anxiolytics, as well as experimental compounds that decrease anxiety in pre-clinical animal models of anxiety, reduce the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in freely behaving or anesthetized animals. In the present experiments, we found that bilateral histamine infusions (0.5 µg/hemisphere) into the lateral septum (LS) of rats decreased anxiety-like responses in two models of anxiety, the elevated plus maze and novelty-induced suppression of feeding test. Surprisingly, these same infusions significantly increased hippocampal theta frequency elicited by reticular stimulation in urethane-anesthetized rats. In contrast to these findings, additional experiments showed that the clinically effective anxiolytic buspirone (40 mg/kg, i.p.) reduced theta frequency, confirming previous observations. Taken together, the dissociation of behavioral anxiolysis and theta frequency reduction noted here suggest that hippocampal theta frequency is not a direct index of anxiety levels in rodents. Further, the mechanisms underlying the behavioral and physiological effects elicited by histamine in the LS require further study.

Infusions of muscimol into the lateral septum do not reduce rats' defensive behaviors toward a cat odor stimulus.

The lateral septum (LS) is implicated in behavioral defense. We tested whether bilateral infusions of the GABAA receptor agonist muscimol into the LS suppress rats' defensive responses to cat odor. Rats received intra-LS infusions of either saline or muscimol (40 ng/rat) and were exposed to either a piece of a cat collar that had been previously worn by a cat or to a control (cat odor free) collar. Rats exposed to the cat odor collar displayed more head-out postures, while intra-LS application of muscimol reduced the number of head-out postures. However, this reduction was also present in rats exposed to a control (cat odor free) collar. This latter finding suggests that despite its involvement in other defensive behaviors (e.g., open arm avoidance in the elevated plus maze), the LS does not selectively regulate rats' receptor defensive responding to the olfactory cues present in our cat odor stimulus.

Child abuse and dentistry: a study of knowledge and attitudes among dentists in Victoria, Australia.

Child abuse is a disturbingly common finding in society today. In view of the high proportion of orofacial injuries seen in victims of child abuse, dentists are in a strategic position to recognize and report suspected cases. The present study of 347 dentists in Victoria, Australia, assessed the level of knowledge and attitudes among dental professionals on the important issue of child abuse. While a high level of interest was shown by the participants towards this issue, a need for further information and training in the recognition and reporting of child abuse was seen in the survey findings. While dentists at present are not legally mandated in all states of Australia to report suspected cases of child abuse, the dental profession is in a key position to play an active role in the identification and reporting of this substantial community problem.

The importance of serum transferrin receptor level in the diagnosis of functional iron deficiency due to recombinant human erythropoietin treatment in haemodialysis patients.

In haemodialysis (HD) patients, functional iron deficiency frequently appears due to recombinant human erythropoietin (r-HuEPO) treatment. However, the diagnosis of iron deficiency is not always easy in such patients. Recent studies have shown that the serum transferrin receptor (s-TfR) level is a sensitive, quantitative measure of tissue iron deficiency. In this study, we examined the changes in s-TfR levels in patients with iron deficiency anaemia due to r-HuEPO treatment. We compared s-TfR levels of 24 patients with i.v. administered r-HuEPO (50-70 U/kg/dose) at the end of each dialysis session (three times a week) and diagnosed as having iron deficiency anaemia by routine laboratory methods (ferritin <50 microg/l and transferrin saturation <16%) with s-TfR levels of 32 patients not receiving r-HuEPO and without iron deficiency anaemia. Also, 40 healthy volunteer subjects were included in the study as a control group. Serum ferritin and transferrin receptor levels were measured with ELISAs using monoclonal reagents. There were no differences between the two groups with and without iron deficiency anaemia with respect to mean age, body weight, haemodialysis duration, haemoglobin and serum creatinine levels (p>0.05). For s-TfR levels, while no difference was present between the control and the non-iron deficiency groups (p>0.05), the iron deficiency group had higher s-TfR values than those of both the control and non-iron deficiency groups (p<0.001). Besides, there was an inverse correlation between haemoglobin and s-TfR levels in patients with iron deficiency anaemia (r = -0.85, p<0.0001). We conclude that the measurement of s-TfR levels may be useful in the diagnosis of functional iron deficiency in haemodialysis patients receiving r-HuEPO.

The histaminergic H1, H2, and H3 receptors of the lateral septum differentially mediate the anxiolytic-like effects of histamine on rats' defensive behaviors in the elevated plus maze and novelty-induced suppression of feeding paradigm.

The neural histaminergic system is involved in a wide range of physiological processes, including anxiety. Histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and share bidirectional connections with the lateral septum, an area well implicated in anxiety. The current study examined whether the histaminergic system of the lateral septum regulates rats' defensive behaviors in two animal models of anxiety, the elevated plus maze (EPM) and novelty-induced suppression of feeding paradigm (NISF). We found that bilateral infusions of histamine (1.0 µg and 5.0 µg) into the lateral septum selectively decreased rats' defensive behaviors in the EPM (both doses) and NISF (1.0 µg only). Follow-up studies found that pre-infusions of the H1 and H2 antagonists, pyrilamine (20 µg) and ranitidine (20 µg) respectively, reversed the anxiolytic-like effects of intra-LS histamine (1.0 µg) in the NISF but not in the EPM, while pre-infusions of the H3 antagonist ciproxifan (200 pg) attenuated the anxiolytic-like effects of intra-LS histamine in the EPM but not in the NISF. This double dissociation suggests that H1 and H2 receptors in the lateral septum, likely via a post-synaptic mechanism, mediate the anxiolytic-like effects of histamine in the NISF but not in the EPM. In contrast, lateral septal H3 receptors mediate, likely pre-synaptically, the anxiolytic-like effects of histamine in the EPM but not in the NISF. Our findings indicate that these receptors differentially contribute to rats' specific defensive behaviors in the EPM and NISF, that is, avoidance of open spaces and neophagia respectively.

Draft genome sequence of the Tibetan antelope.

The Tibetan antelope (Pantholops hodgsonii) is endemic to the extremely inhospitable high-altitude environment of the Qinghai-Tibetan Plateau, a region that has a low partial pressure of oxygen and high ultraviolet radiation. Here we generate a draft genome of this artiodactyl and use it to detect the potential genetic bases of highland adaptation. Compared with other plain-dwelling mammals, the genome of the Tibetan antelope shows signals of adaptive evolution and gene-family expansion in genes associated with energy metabolism and oxygen transmission. Both the highland American pika, and the Tibetan antelope have signals of positive selection for genes involved in DNA repair and the production of ATPase. Genes associated with hypoxia seem to have experienced convergent evolution. Thus, our study suggests that common genetic mechanisms might have been utilized to enable high-altitude adaptation.

Transcriptome and network changes in climbers at extreme altitudes.

Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.

Lesions of the dorsal lateral septum do not affect neophagia in the novelty induced suppression of feeding paradigm but reduce defensive behaviours in the elevated plus maze and shock probe burying tests.

Past studies have shown that the lateral septum is involved in anxiety. Here, we tested whether the dorsal lateral septum contributes to neophagia by using the novelty induced suppression of feeding (NISF) paradigm. We found that while lesions of the dorsal lateral septum did not affect home or novel cage responding in the NISF test, they did decrease open arm avoidance in the elevated plus maze and burying in the shock probe burying test. Our results suggest that the dorsal lateral septum does not regulate neophagia in the NISF, but further experiments are needed to determine if the same is true for the intermediate and ventral lateral septum.

Plasma atrial natriuretic peptide and its relation to the renin-angiotensin-aldosterone system in patients with chronic renal failure.

To determine the relationship between plasma immunoreactive atrial natriuretic peptide (i-ANP) and renin-angiotensin-aldosterone system (RAAS), plasma i-ANP, plasma renin activity (PRA) and plasma aldosterone (PA) were assayed in 29 patients (19 hypertensive and 10 normotensive) with chronic renal failure (CRF), and in 10 healthy subjects. Hypertensive patients had higher i-ANP values than normotensive patients and controls (P less than 0.05 and P less than 0.01 respectively). There was no significant correlation between plasma i-ANP and creatinine concentrations in hypertensive patients, whereas this correlation was statistically significant in normotensive patients (r = 0.70, P less than 0.01). Other positive correlations were between plasma i-ANP and systolic blood pressure in hypertensive patients (r = 0.69, P less than 0.01) and between plasma ANP and mean arterial pressure in normotensive patients (r = 0.63, P less than 0.01). There was significant negative correlation between plasma ANP and fractional sodium excretion (FENa) in hypertensive patients (r = -0.47, P less than 0.05), though there was significant positive correlation in normotensive patients (r = 0.80, P less than 0.01). Hypertensive patients, with the exception of one anuric patient and another with atrial fibrillation, had a significant negative correlation between FENa and systolic arterial blood pressure (r = 0.64, P less than 0.01). The patient group had increased PRA and PA values (P less than 0.01 and P less than 0.001 respectively) and showed positive correlation with mean arterial pressure (MAP) (r = 0.71, P less than 0.001 and r = 0.58, P less than 0.01 respectively). These results show that increased concentrations of immunoreactive ANP circulate in CRF together with activated RAAS. We demonstrate that elevated ANP cannot affect blood pressure and natriuresis in hypertensive patients with CRF, whose RAAS is activated.

Spontaneous bilateral rupture of kidneys in a patient with polyarteritis nodosa. A case report.

A previously well 42-year-old man presented with a three-hour history of pain in the right flank of acute onset. At laparotomy he was found to have a ruptured right kidney which was treated by nephrectomy. Eight days later he developed similar symptoms on the left: at operation 21 of blood were drained and nephrostomy and catheterisation carried out. He recovered after a complicated postoperative course, and histological examination of the removed kidney, and biopsy specimens, showed classic polyarteritis nodosa. This is a rare cause of spontaneous rupture of the kidney but must be considered whenever a patient presents with renal haemorrhage of unknown cause.

Outcome of pregnancies with HELLP syndrome complicated by acute renal failure (1989-1999).

HELLP syndrome, a syndrome of hemolysis, elevated liver enzymes and low platelets may occur in pregnancy with pre-eclampsia/eclampsia, and its a significant complication is acute renal failure (ARF). The aim of study was to determine frequency and outcome of HELLP syndrome complicated by ARF. Thirty-nine patients with pregnancy-related ARF were treated between Jan 1, 1989 and Jan 1, 1999. In these patients, the most frequent causes were HELLP syndrome (n = 14; 36%), postpartum hemorrhage (n = 10; 26%), pre-eclampsia/eclampsia (n = 6; 15%) and abruptio placenta (n = 4; 10%). Seven of the patients with HELLP syndrome had impairment of consciousness during hospitalization. Of these patients, coma in 5, stupor in 1, confusion in 1 were diagnosed. Twelve of the patients with HELLP syndrome and 14 of the other patients were treated by dialysis. Mann-Whitney U test and chi2 test(corrected by Yates and Fisher exact) were used for statistical analysis. Although serious clinical findings, with supportive treatment, 12 patients with HELLP syndrome and 21 other patients were fully recovered. One patient both with and without HELLP syndrome could not recovered due to diffuse cortical necrosis. Moreover, one patient with HELLP syndrome and 3 other patients were died. Mortality rate of the patients with HELLP syndrome was not found different from those of the other patients (p = 0.544). The causes of death were cerebral hemorrhage in patient with HELLP syndrome and disseminated intravascular coagulation (n = 1), cerebral emboli (n = 1), adult respiratory distress syndrome (n = 1). Fetal death occurred in 4 patients with HELLP syndrome (28.5%) and 7 other patients (28%), and rates were similar (p > 0.5). Finally, HELLP syndrome was the most frequent cause leading to ARF in pregnancy and their prognosis was not different from those of the other patients.

Changes in frequency and etiology of acute renal failure in pregnancy (1980-1997).

In recent years, the incidence of acute renal failure (ARF) in pregnancy has decreased in developed countries. This cause of this decline has been reported to be liberalized abortion laws and improved prenatal care. The aim of this study was to determine if the incidence and etiology of ARE in pregnancy in our population had undergone similar changes. Between January 1, 1980 and January 1 1997 the number of the patients with ARF was 487. In 74 (15%) of these patients, the etiology of ARF was associated with pregnancy. The frequency of ARF in pregnancy was 17.4% between January 1980 and August 1985, 15.4% between September 1985 and November 1989, 13.5% between December 1989 and January 1997. The differences between the frequencies were not statistically significant (p > 0.5). In the present series, the various disorders leading to ARF in pregnancy were abortion (30%), HELP syndrome and pre-eclampsia (14%), pre-eclampsia or eclampsia (12%), postpartum hemorrhage (15%), fetal death (12%), abruption placentae (6%) and placentae previa (1%).

Frequency and outcome of patients with acute renal failure have more causes than one in etiology.

In literature, there was little data about frequency and outcome of ARF with two or more causes in etiology. Therefore, the aim of this study was to search this issue. This series included 339 patients with ARF from Jan 1,1987 to Jan 1,1999. Fourty-six (30 males) of all patients (13.5%) had two or more causes in etiology of ARF. Of these patients, causes were prerenal and renal in 26 (56%), prerenal, renal and postrenal in 12 (26%), renal and postrenal in 4 (9%), and prerenal and postrenal in 4 (9%). The most frequent cause is diarrhea and vomiting in prerenal, gentamycin usage in renal and prostate hypertrophy in postrenal. Of these patients, there was oliguria in 32 (70%), anuria in 8 (17%) and non-oliguria in 6 (13%). Treatment modalities of patients was only medical in 19 (41%), dialysis in addition to medical therapy in 27 (59%). In spite of treatment, 5 (10.8) of patients with two or more causes in etiology died. Causes of death were uremic coma in 2, cardiac disorders in 2 and septic shock in 1. Three (11.2%) of other patients with one cause died. Mortality rates were not different (chi2: 0.0298, p > 0.5). Cortical necrosis was diagnosed in one patient with multiple etiology and 2 of other patients. Finally, frequency of ARF with two or more etiologic causes was 13.5%, and most frequent causes were hypovolemia and nephrotoxic drugs. Outcome of these patients was similar to other patients with one cause.