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Background Rectal cancer is commonly treated by chemoradiation therapy, followed by the low anterior resection anal sphincter-preserving surgery, with a temporary protecting ileostomy. After reversal of the stoma a condition known as low anterior resection syndrome (LARS) can occur characterized by a combination of symptoms such as urgent bowel movements, lack of control over bowel movements, and difficulty fully emptying the bowels. These symptoms have a significant negative impact on the quality of life for individuals who have survived the cancer. Currently, there is limited available data regarding the presence, risk factors, and effects of treatment for these symptoms during long-term follow-up. Aims To evaluate long term outcomes of low anterior resection surgery and its correlation to baseline anorectal manometry (ARM) parameters and physiotherapy with anorectal biofeedback (BF) treatment. Methods One hundred fifteen patients (74 males, age 63 ± 11) who underwent low anterior resection surgery for rectal cancer were included in the study. Following surgery, patients were managed by surgical and oncologic team, with more symptomatic LARS patients referred for further evaluation and treatment by gastroenterologists. At follow up, patients were contacted and offered participation in a long term follow up by answering symptom severity and quality of life (QOL) questionnaires. Results 80 (70%) patients agreed to participate in the long term follow up study (median 4 years from stoma reversal, range 1–8). Mean time from surgery to stoma closure was 6 ± 4 months. At long term follow up, mean LARS score was 30 (SD 11), with 55 (69%) patients classified as major LARS (score > 30). Presence of major LARS was associated with longer time from surgery to stoma reversal (6.8 vs. 4.8 months; p  = 0.03) and with adjuvant chemotherapy (38% vs. 8%; p  = 0.01). Patients initially referred for ARM and BF were more likely to suffer from major LARS at long term follow up (64% vs. 16%, p  < 0.001). In the subgroup of patients who underwent perioperative ARM ( n  = 36), higher maximal squeeze pressure, higher maximal incremental squeeze pressure and higher rectal pressure on push were all associated with better long-term outcomes of QOL parameters ( p  < 0.05 for all). 21(54%) of patients referred to ARM were treated with BF, but long term outcomes for these patients were not different from those who did not perform BF. Conclusions A significant number of patients continue to experience severe symptoms and a decline in their quality of life even 4 years after undergoing low anterior resection surgery. Prolonged time until stoma reversal and adjuvant chemotherapy emerged as the primary risk factors for a negative prognosis. It is important to note that referring patients for anorectal physiology testing alone tended to predict poorer long-term outcomes, indicating the presence of selection bias. However, certain measurable manometric parameters could potentially aid in identifying patients who are at a higher risk of experiencing unfavorable functional outcomes. There is a critical need to enhance current treatment options for this patient group.

This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease. British Journal of Pharmacology (2007) 152, 1155–1171; doi:10.1038/sj.bjp.0707354; published online 9 July 2007

Orphan cytochrome P450 (CYP) enzymes are those for which biological substrates and function(s) are unknown. Cytochrome P450 20A1 (CYP20A1) is the last human orphan P450 enzyme, and orthologs occur as single genes in every vertebrate genome sequenced to date. The occurrence of high levels of CYP20A1 transcripts in human substantia nigra and hippocampus and abundant maternal transcripts in zebrafish eggs strongly suggest roles both in the brain and during early embryonic development. Patients with chromosome 2 microdeletions including CYP20A1 show hyperactivity and bouts of anxiety, among other conditions. Here, we created zebrafish cyp20a1 mutants using CRISPR/Cas9, providing vertebrate models with which to study the role of CYP20A1 in behavior and other neurodevelopmental functions. The homozygous cyp20a1 null mutants exhibited significant behavioral differences from wild-type zebrafish, both in larval and adult animals. Larval cyp20a1 -/- mutants exhibited a strong increase in light-simulated movement (i.e., light–dark assay), which was interpreted as hyperactivity. Further, the larvae exhibited mild hypoactivity during the adaptation period of the optomotor assays. Adult cyp20a1 null fish showed a pronounced delay in adapting to new environments, which is consistent with an anxiety paradigm. Taken together with our earlier morpholino cyp20a1 knockdown results, the results described herein suggest that the orphan CYP20A1 has a neurophysiological role.

Previous studies have demonstrated a negative correlation between intestinal alkaline phosphatase (IAP) activity and calcium (Ca) absorption in the gut, as IAP acts as a protective mechanism inhibiting high Ca entry into enterocytes, preventing Ca overload. Here we evaluated Ca absorption and bone properties in knockout mice (KO) completely devoid of duodenal IAP (Akp3−/− mice). Female C57BL/6 control mice (WT, n = 7) and KO mice (n = 10) were used to determine Ca absorption in vivo and by in situ isolated duodenal loops followed by histomorphometric analysis of duodenal villi and crypts. Bone mineral density, morphometry, histomorphometry and trabecular connectivity and biomechanical properties were measured on bones. We observed mild atrophy of the villi with lower absorption surface and a significantly higher Ca uptake in KO mice. While no changes were seen in cortical bone, we found better trabecular connectivity and biomechanical properties in the femurs of KO mice compared to WT mice. Our data indicate that IAP KO mice display higher intestinal Ca uptake, which over time appears to correlate with a positive effect on the biomechanical properties of trabecular bone.

Background The role of factor XIII in acute bleeding situations is gaining more and more importance. It has previously been shown that prepartum factor XIII activity has a significant impact on postpartum blood loss. Whether factor XIII antigen behaves in a similar manner is unknown. As postpartum hemorrhage is one of the leading causes of maternal morbidity and mortality worldwide and factor XIII antigen determination might be available more readily in some centers as compared to factor XIII activity, this is an important question to answer, especially in the emergency situation of a postpartum hemorrhage. Objective To assess the correlation of prepartum factor XIII antigen with prepartum factor XIII activity and to evaluate the correlation between prepartum factor XIII antigen on measured postpartum blood loss. Methods This is a secondary analysis of a prospective cohort study which analyzed the impact of prepartum blood coagulation factor XIII activity on postpartum blood loss in 1300 women at the University Hospital Zurich, Switzerland between October 2015 and November 2016 (“ PPH-1300 study ”). Blood loss was quantified using a previously validated technique. The association of factor XIII activity and factor XIII antigen was assessed by means of a Spearman rank correlation and differences were displayed using Bland–Altman plot and Passing–Bablok regression. The effect of the prepartum factor XIII antigen on blood loss was estimated by continuous outcome logistic regression. Results Prepartum factor XIII activity significantly correlated with prepartum factor XIII antigen (Spearman rank correlation coefficient for prepartum values 0.89, p  < 0.001 and postpartum values 0.902, p  < 0.001). Elevated values of prepartum factor XIII antigen showed a trend toward lower measured postpartum blood loss. Conclusion The correlation of factor XIII activity with factor XIII antigen (subunit A) in a large real-world sample as well as an association of prepartum factor XIII antigen and postpartum blood loss is observed. Factor XIII antigen determination, a highly automatable test, could be useful in emergency situations such as a PPH (as well as other bleeding situations) if the determination of factor XIII activity is not possible. To evaluate whether FXIII replenishment reduces blood loss is the focus of ongoing studies.

A theoretical model based on a quasi-one-dimensional formulation is developed which allows determination of the shock stand-off distance at the stagnation point of blunt bodies in hypersonic non-equilibrium flows. Despite the simple ideal dissociating gas model implemented in the theoretical approach, it gives insight into the main physics governing the shock stand-off problem. More detailed and precise data are obtained by a numerical simulation where vibrational and chemical relaxation processes as well as their interactions are taken into account. The physical modelling of these processes is based on a kinetic approach and on a generalized Chapman–Enskog method of solving the Boltzmann equation. Explicit formulae for rate constants and vibrational energy consumption are derived and incorporated into the general conservation equations. Good agreement between theoretical, numerical and experimental results is achieved which ensures a reliable and mutual validation of the different methods.

Intestinal alkaline phosphatase (IAP) is a brush-border phosphomonoesterase. Its location suggests an involvement in the uptake of nutrients, but its role has not yet been defined. IAP expression parallels that of other proteins involved in Ca absorption under vitamin D stimulation. Experiments carried out in vitro with purified IAP have demonstrated an interaction between Ca and IAP. The gut is prepared to face different levels of Ca intake over time, but high Ca intake in a situation of a low-Ca diet over time would cause excessive entry of Ca into the enterocytes. The presence of a mechanism to block Ca entry and to avoid possible adverse effects is thus predictable. Thus, in the present study, Sprague–Dawley rats were fed with different amounts of Ca in the diet (0·2, 1 and 2 g%), and the percentage of Ca absorption (%Ca) in the presence and absence of l -phenylalanine (Phe) was calculated. The presence of Phe caused a significant increase in %Ca (52·3 ( sem 6·5) % in the presence of Phe v . 31·1 ( sem 8·9) % in the absence of Phe, regardless of the amount of Ca intake; paired t test, P  = 0·02). When data were analysed with respect to Ca intake, a significant difference was found only in the group with low Ca intake (paired t test, P  = 0·03). Additionally, IAP activity increased significantly (ANOVA, P  < 0·05) as Ca concentrations increased in the duodenal lumen. The present study provides in vivo evidence that luminal Ca concentration increases the activity of IAP and simultaneously decreases %Ca, acting as a minute-to-minute regulatory mechanism of Ca entry.

Purpose. To evaluate the effect of teriparatide (TPTD) on bone mineral density (BMD) and bone markers under clinical practice conditions. To assess whether the results in real-life match those published in clinical trials. Methods. Cross-sectional study of postmenopausal women treated with TPTD for at least 12 months. Results. 264 patients were included in the study. Main characteristics are as follows: age: 68.7 ± 10.2 years, previous fractures: 57.6%, and previously treated with antiresorptive (AR-prior): 79%. All bone turnover markers studied significantly increased after 6 months. CTX and BGP remained high up to 24 months, but total and bone alkaline phosphatase returned to basal values at month 18. There was a significant increase in lumbar spine (LS) BMD after 6 months (+6.2%), with a maximum peak at 24 months (+13%). Femoral neck (FN) and total hip (TH) BMD showed a significant increase later than LS (just at month 12), reaching a maximum peak at month 24 (FN + 7.9% and TH + 5.5%). A significant increase in LS BMD was found from month 6 to month 24 compared to basal in both AR-naïve, and AR-prior patients (+16.7% and +10.5%, respectively), without significant differences between the two groups. Comparable results were found in FN and TH BMD. Main conclusions. As reported in real-life clinical studies, treatment of osteoporotic postmenopausal women with TPTD induced a significant increase in bone turnover markers from month 6 onward and an increase in BMD from months 6–12 with continuous gain up to month 24. The real-life results of our study matched the results of randomized clinical trials. In addition, TPTD induced an increase in BMD, regardless of the previous use of AR.

The most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to neurotoxic chemicals can result in neurobehavioral disorders. In this study, we uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits using zebrafish as a vertebrate model. We investigated the effects of the abundant non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. Morphological and biochemical data demonstrate that even though PCB153-induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling appears to contribute to PCB-induced motor deficits. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and increased selection pressures in vertebrate wildlife.Nadja Brun et al. characterize the impact of early exposure to polychlorinated biphenyls on neural development and behavior in zebrafish. Their results demonstrate that developmental exposure to these chemicals promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in larval zebrafish, suggesting that these chemicals may also contribute to neurodevelopmental abnormalities in humans.