Successful treatment of idiopathic secretory diarrhea of infancy with the somatostatin analogue SMS 201-995

The somatostatin analogue SMS 201-995 has been reported to be effective in treating adult secretory diarrhea due to vasoactive intestinal polypeptidoma. We report the effectiveness of this drug in treating severe refractory secretory diarrhea of uncertain etiology in an infant. The patient developed diarrhea within the first few days of life, with mean stool output of 250 ml/kg.day (expected 10 ml/kg.day). Small bowel biopsy showed mild focal enteritis. Serum levels of known gastrointestinal secretagogues were normal. No tumor was detected. Diarrhea was not adequately controlled by various drug treatments. Addition of subcutaneous SMS 201-995 produced a significant sustained decrease in stool output to 80-100 ml/kg.day. During SMS 201-995 treatment, no metabolic, hormonal, or growth abnormalities were noted. SMS 201-995 was discontinued after 9 mo because of patient irritability. Stool output rose immediately to 173 ml/kg.day, and remained stable for 6 mo. It is concluded that SMS 201-995 was a safe and effective treatment in this single childhood case of severe idiopathic secretory diarrhea.     

Distribution of corticotrophin releasing factor activity within the hypothalamic-pituitary complex of rats and cattle.

An assay system involving cultured rat adenohypophysial cells from either intact or adrenalectomized donors was used to study the distribution of corticotrophin releasing factor (CRF) activity in the hypothalamic-pituitary complex of rats and cattle. In the rat hypothalamus, CRF activity was most concentrated in the median eminence, but CRF was present in the stalk and the posterior pituitary gland in much higher concentrations than in the median eminence in both species. The dose--response slopes for the median eminence, stalk and pars nervosa of the posterior pituitary gland were parallel to each other, suggesting a qualitative similarity between the CRF activity in these tissues. Rat posterior pituitary glands may also contain another CRF component which has a much flatter dose--response curve, but is detectable in smaller quantities of posterior pituitary tissue than is the other type of CRF.     

G(o) protein-dependent survival of primary accessory olfactory neurons

Extensive G protein-coupled receptor families in both the main and accessory olfactory systems have been implicated in axonal targeting, sensory function, and cell survival. Although sensory function seems to be mediated by G proteins, axonal guidance and cell survival may be G protein-independent processes. In the accessory olfactory system, the G(o)-containing neurons in the basal vomeronasal organ (VNO) project to the posterior accessory olfactory bulb (AOB), whereas more apically located VNO neurons contain G(i2) and project to the anterior AOB. Herein, we investigate the organization of the accessory olfactory system in mice with a targeted deletion in the G(o)alpha gene. The accessory olfactory system seems normal at birth; however, postnatally, the number of G(o)-receptor-containing VNO neurons decreases by half, and apoptotic neurons are detected. The axons of VNO neurons remain restricted to the posterior AOB. The posterior AOB is reduced in size but contains a synaptophysin-positive layer with the normal number of glomeruli. The posterior AOB has reduced mitral cell c-Fos immunoreactivity, consistent with decreased sensory activation of G(o) protein-coupled VNO receptor neurons. Thus, in the accessory olfactory system, receptor-coupled G proteins are required for cell survival.     

Low-molecular-weight heparin for the prevention and treatment of venous thromboembolism in pregnancy

PURPOSE OF REVIEW: Low-molecular-weight heparins (LMWHs) have largely replaced unfractionated heparins for both prophylaxis and treatment of venous thromboembolism in nonpregnant patients. However, until recently, evidence in pregnant women was lacking, despite the increasing use of LMWHs during pregnancy in clinical practice. This review covers recent literature on the use of LMWHs in relation to pregnancy. RECENT FINDINGS: The main areas covered in this review are the use of LMWHs in both prophylaxis and treatment of venous thromboembolism in pregnancy. The review also considers issues relating to monitoring of LMWHs in pregnancy, and safety from both a maternal and a fetal perspective. SUMMARY: The available evidence demonstrates that LMWHs are of at least equivalent efficacy but have a better safety profile compared with unfractionated heparins in both prophylaxis and treatment of maternal venous thromboembolism, and are more convenient to administer. There is no consensus with respect to whether these agents require monitoring during pregnancy other than periodic checking of the platelet count. The clinical implication from the available evidence is that LMWHs should now be regarded as the anticoagulant agents of choice for both prophylaxis and treatment of maternal venous thromboembolism.     

Microstructure provides insights into evolutionary design and resilience of Coscinodiscus sp. frustule

We conducted in situ three-point bending experiments on beams with roughly square cross-sections, which we fabricated from the frustule of Coscinodiscus sp. We observe failure by brittle fracture at an average stress of 1.1 GPa. Analysis of crack propagation and shell morphology reveals a differentiation in the function of the frustule layers with the basal layer pores, which deflect crack propagation. We calculated the relative density of the frustule to be ∼30% and show that at this density the frustule has the highest strength-to-density ratio of 1,702 kN⋅m/kg, a significant departure from all reported biologic materials. We also performed nanoindentation on both the single basal layer of the frustule as well as the girdle band and show that these components display similar mechanical properties that also agree well with bending tests. Transmission electron microscopy analysis reveals that the frustule is made almost entirely of amorphous silica with a nanocrystalline proximal layer. No flaws are observed within the frustule material down to 2 nm. Finite element simulations of the three-point bending experiments show that the basal layer carries most of the applied load whereas stresses within the cribrum and areolae layer are an order of magnitude lower. These results demonstrate the natural development of architecture in live organisms to simultaneously achieve light weight, strength, and exceptional structural integrity and may provide insight into evolutionary design.Diatoms are single-cell algae that form a hard cell wall made of a silica/organic composite. The ability to produce a functional biosilica shell presents several natural precedents that fascinate and inspire scientists and engineers. One fascinating aspect of such silica glass shells is their intricate, varied, and detailed architecture. Diatoms are generally classified based on the symmetry of their shells: Centric diatoms display radial symmetry whereas pennate diatoms have bilateral symmetry. Fig. 1A shows a schematic of a typical centric diatom and reveals that the shells are composed of two halves, called frustules, that fit together in a Petri-dish configuration. The frustules are attached to each other around the perimeter of the shell by one or several girdle bands. The frustules are usually porous with pore size and density varying between species. The frustule shell can also be composed of multiple layers with a cellular structure within the shell.Open in a separate windowFig. 1.(A) Schematic of the diatom frustule shell. (B) Cross-section of shell demonstrating the honeycomb sandwich plate configure of the silica shell. (C) Cribrum, the outer layer of the frustule shell, displays hexagonal arrangements of pores. (D) The basal plate, the inner layer of the frustule shell, is punctuated by reinforced pores called foramen.The proposed evolutionary functions for these intricate shell designs include nutrient acquisition, control of diatom sinking rate, control of turbulent flow around the cell, and protection from grazing and viral attack (1). Evidence in favor of a protective function is that the degree of shell silification depends on the environment, with greater amounts of silica found in shells grown in a predatory environment (2). As a deterrent to predation, the frustule makes use of an inherently brittle glass as a structurally protective material while balancing other evolutionary pressures. A denser shell may provide greater protection but will cause the diatom to sink beyond depths suitable for photosynthesis. A solid shell might also prevent exchange of resources and waste between the diatom cell and its environment. This requires adaption through control of the frustule micromorphology or modification of the constituent silica/organic composite material (3). The protective aspects of the frustule shell are clear; what remains an open question is how much the intricate pore structure and cellular design contribute to the amplified structural resilience vs. biological function.The size of most diatom species ranges from 2 to 200 µm (4, 5), which renders most of the traditional mechanical testing methods inadequate to characterize such complex materials; a few mechanical studies on diatoms have been reported (6–11). The majority of studies perform atomic force microscopy (AFM) indentation (6–9) on a full frustule of centric or pennate diatoms. Reported values of hardness ranged from 0.06–12 GPa and values of elastic modulus from 0.35–22.4 GPa. Differences in local pore structure and the nonplanar geometry of the frustule were often cited for the variance in mechanical properties. Three-point bending tests on beams that were extracted from the diatom frustule reported failure strengths of 336 ± 73 MPa but were complicated by local penetration of the indenter tip and tilting of the frustule during testing (10, 11).This overview demonstrates a wide range in the reported hardnesses and elastic moduli for biosilica shells. Most of these experiments were performed on full diatom shells, which in some instances contained organic cellular material; it is unclear whether the measured mechanical data represent the deformation of the constituent biosilica or the overall deformation of the shell through bending, local twisting, pivoting, and so on. Indentation using AFM can introduce inaccuracies such as tip sliding, and the resulting uncertainty in compliance within a single set of experiments, as well as among the data obtained with different instruments, makes it challenging to compare mechanical properties of the diatoms across the reported experiments. Within a single species, these mechanical data may provide qualitative trends in the structural response of the diatom shells; it is difficult to make any conclusions on the mechanical properties of the constituent biosilica. The mechanisms of silica biogenesis likely varies among the species (12), but it is unclear to what extent these differences reflect the variation in elastic modulus and hardness between species and within an individual frustule.To investigate the mechanical properties of the diatom frustule and constituent biosilica as decoupled from the full-shell structural response, we conducted in situ three-point bending experiments on beams with roughly 3.5-µm-square cross-sections fabricated from the frustule of Coscinodiscus sp. performed in a scanning electron microscope (SEM) equipped with a nanoindenter, as well as ex situ nanoindentation on an individual basal plate that had been isolated from a frustule and the girdle band. We determined the elastic modulus to be 36.4 ± 8.3 GPa and the failure strength to be 1.1 ± 0.3 GPa. We discuss these results, as well as deformation and failure mode of the diatoms, in the context of their atomic-level microstructure obtained from transmission electron microscopy (TEM) and finite element method (FEM) simulations of the three-point bending tests.     

Transit dosimetry in dynamic IMRT with an a-Si EPID

Using an amorphous silicon (a-Si) EPID for transit dosimetry requires detailed characterization of its dosimetric response in a variety of conditions. In this study, a measurement-based model was developed to calibrate an a-Si EPID response to dose for transit dosimetry by comparison with a reference ionization chamber. The ionization chamber reference depth and the required additional buildup thickness for electronic portal imaging devices (EPID) transit dosimetry were determined. The combined effects of changes in radiation field size, phantom thickness, and the off-axis distance on EPID transit dosimetry were characterized. The effect of scattered radiation on out-of-field response was investigated for different field sizes and phantom thicknesses by evaluation of the differences in image profiles and in-water measured profiles. An algorithm was developed to automatically apply these corrections to EPID images based on the user-specified field size and phantom thickness. The average phantom thickness and an effective field size were used for IMRT fields, and images were acquired in cine mode in the presence of an anthropomorphic phantom. The effective field size was defined as the percentage of the jaw-defined field that was involved during the delivery. Nine head and neck dynamic IMRT fields were tested by comparison with a MatriXX two-dimensional array dosimeter using the Gamma (3 %, 3 mm) evaluation. A depth of 1.5 cm was selected as the ionization chamber reference depth. An additional 2.2 mm of copper buildup was added to the EPID. Comparison of EPID and MatriXX dose images for the tested fields showed that using a 10 % threshold, the average number of points with Gamma index <1 was 96.5 %. The agreement in the out-of field area was shown by selection of a 2 % threshold which on average resulted in 94.8 % of points with a Gamma index <1. The suggested method is less complicated than previously reported techniques and can be used for all a-Si EPIDs regardless of the manufacturer.     

Microscopic inflammatory foci in burn scars: data from a porcine burn model

Background: Hypertrophic scars in burn victims usually occur after delayed wound healing and the active phase of scar formation can persist substantially even after wound closure. Currently, the pathophysiology of the hypertrophic scar is not completely understood. This study investigated the inflammatory response in scar tissue at week 6 post‐burn injury. Methods: A porcine deep dermal partial thickness burn model was used. At week 6 post‐burn, a total of 528 scar biopsies from 72 burn scars (7–8 biopsies from each scar) and 174 normal skin biopsies from 18 pigs were collected and examined histologically. Results: Microscopic inflammatory foci were identified in 17% (89/528) of scar biopsies. These microscopic inflammatory foci do not contain any irritant materials, are composed largely of polymorphonuclear cells with other inflammatory cells including multinucleate giant cells and show acute on chronic inflammatory response that has not been described previously in burn scars. Importantly, they are present in a significantly lower number in burns surgically debrided than in burns which have not been debrided. Conclusions: This study identifies microscopic inflammatory foci in the porcine scar tissue layer and recommends thorough cleaning/debriding of burned necrotic tissue in order to minimize the formation of these inflammatory foci in scar tissue. Wang X‐Q, Phillips GE, Wilkie I, Greer R, Kimble RM. Microscopic inflammatory foci in burn scars: data from a porcine burn model.