Co-occurrence of IgE and IgG autoantibodies in patients with chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) pathogenesis shows a complex and still unclear interplay between immunoglobulin (Ig)G- and IgE-mediated autoimmunity, leading to mast cell and basophil degranulation and wheal formation. The objective of this study was to evaluate at the same time IgE- and IgG-reactivity to well recognized and recently reported autoantigens in CSU patients, and to assess the effects of such reactivity on response to the anti-IgE monoclonal antibody omalizumab. Twenty CSU patients underwent omalizumab treatment. Urticaria activity score 7 (UAS7) was recorded at baseline and at different drug administration time-points for categorizing early-, late- or non-responders. At baseline, sera from the 20 patients and from 20 controls were tested for IgE and IgG autoantibodies to high- and low-affinity IgE receptors (FcεRI and FcεRII), tissue factor (TF) and thyroglobulin (TG) by immunoenzymatic methods. Antibody levels were compared with those of controls and analysed according to response. Eighteen patients were omalizumab responders (11 early and seven late), while two were non-responders. More than 50% of patients had contemporary IgE and IgG to at least to one of the four different autoantigens. Late responders showed higher levels of both anti-TF IgE and IgG than early responders (P = 0·011 and P = 0·035, respectively). Twenty-five per cent of patients had levels of anti-FcεRI IgE, exceeding the upper normal limit, suggesting that it could be a novel auto-allergen in CSU. In CSU, there is an autoimmune milieu characterized by the co-existence of IgE and IgG autoantibodies to the same antigen/allergen, particularly in late responders to omalizumab, possibly explaining the slower response.     

Multimorbidity and functional impairment–bidirectional interplay,synergistic effects and common pathways

This review discusses the interplay between multimorbidity (i.e. co‐occurrence of more than one chronic health condition in an individual) and functional impairment (i.e. limitations in mobility, strength or cognition that may eventually hamper a person's ability to perform everyday tasks). On the one hand, diseases belonging to common patterns of multimorbidity may interact, curtailing compensatory mechanisms and resulting in physical and cognitive decline. On the other hand, physical and cognitive impairment impact the severity and burden of multimorbidity, contributing to the establishment of a vicious circle. The circle may be further exacerbated by people's reduced ability to cope with treatment and care burden and physicians’ fragmented view of health problems, which cause suboptimal use of health services and reduced quality of life and survival. Thus, the synergistic effects of medical diagnoses and functional status in adults, particularly older adults, emerge as central to assessing their health and care needs. Furthermore, common pathways seem to underlie multimorbidity, functional impairment and their interplay. For example, older age, obesity, involuntary weight loss and sedentarism can accelerate damage accumulation in organs and physiological systems by fostering inflammatory status. Inappropriate use or overuse of specific medications and drug–drug and drug–disease interactions also contribute to the bidirectional association between multimorbidity and functional impairment. Additionally, psychosocial factors such as low socioeconomic status and the direct or indirect effects of negative life events, weak social networks and an external locus of control may underlie the complex interactions between multimorbidity, functional decline and negative outcomes. Identifying modifiable risk factors and pathways common to multimorbidity and functional impairment could aid in the design of interventions to delay, prevent or alleviate age‐related health deterioration; this review provides an overview of knowledge gaps and future directions.     

Dynamic spin-echo MRI of liver cancer using Gadolinium-DTPA: animal investigation

An animal model of liver cancer was used to demonstrate that with a fast MRI technique, Gadolinium-DTPA increases tumor-liver contrast. A spin-echo pulse sequence with short repetition (TR) and echo-delay (TE) times (TR 250/TE 15/Excitations 1) has a scan time of 0.6 min, which allows early dynamic postcontrast infusion imaging. This is necessary to capture peak compartmental differences when an extracellular contrast agent such as Gadolinium-DTPA is used. This short TR/short TE pulse sequence also increases T1-dependent tissue contrast over the traditional (inversion recovery or spin echo) T1-weighted pulse sequences. Our studies suggest a significant potential for improved detection of liver metastases with Gadolinium-DTPA-enhanced liver MRI.     

Percutaneous obliteration of the cystic duct with a holmium:yttrium-aluminum-garnet laser: results of in vitro and animal experiments.

OBJECTIVE. The purpose of this study was to investigate the feasibility of using a holmium:yttrium-aluminum-garnet laser to permanently occlude the cystic duct in order to isolate the gallbladder from the biliary-enteric circulation and prevent gallstone formation. MATERIALS AND METHODS. To determine the optimal laser parameters (power and pulsing rate) for cystic duct thermocoagulation, 20 freshly excised porcine gallbladders with intact cystic ducts underwent low-energy (0.075-0.085 J/pulse) or high-energy (0.20-0.25 J/pulse) thermocoagulation. Histopathologic examination was done to determine the extent of cystic duct injury. After in vitro experiments, percutaneous transcholecystic laser thermocoagulation of the cystic duct was performed on 23 anesthetized domestic pigs (four controls). Cholangiograms immediately after laser thermocoagulation were obtained to assess cystic duct occlusion. Animals were sacrificed for histopathologic correlation immediately after laser thermocoagulation (n = 4), 72 hr later (n = 4), and 6 weeks later (n = 15). RESULTS. In the in vitro studies, all 10 cystic ducts in the high-energy group were occluded, while only four in the low-energy group were occluded. At histology, all cases in both groups showed circumferential injury to the cystic duct wall without injury to the cystic artery or vein. In the in vitro experiments, the cystic duct was successfully cannulated in 21 (91%) of 23 animals. Cholangiography after thermocoagulation showed occlusion of the cystic duct in 16 (84%) of 19 cases. Immediately after laser thermocoagulation, the cystic duct mucosa was circumferentially destroyed, whereas after 72 hr necrosis of the cystic duct wall and periductal tissues had occurred. By 6 weeks, all pigs had complete cystic duct fibrosis without injury to the common bile duct. CONCLUSION. Holmium:yttrium-aluminum-garnet laser thermocoagulation of the cystic duct can be performed easily, results in immediate cystic duct occlusion, and leads to permanent fibrous ductal obliteration by 6 weeks.     

MR imaging of focal splenic tumors

This study was undertaken to define the MR appearance of splenic tumors in 16 cancer patients with focal splenic lesions; 50 volunteers and liver cancer patients without splenic abnormalities served as controls. In 14 patients with focal splenic lesions, differences between splenic and lesion signal intensities permitted detection of splenic lesions on MR images, either because of cystic or necrotic areas lengthening T2 within the tumor, because of T1 shortening from tumor-associated hemorrhage, or because of T2 shortening of surrounding spleen in two cases of suspected transfusional iron overload. In one spleen, a lesion appeared isointense on both T1- and T2-weighted pulse sequences and was detected only by gross splenic deformity. In one other case, CT defined splenic metastases not visible on MR images. Measurements of signal intensity of normal spleens and tumor are so similar that spin-echo MR imaging can underestimate the size and extent of focal splenic disease or may miss lesions entirely. We conclude that MR imaging is a less sensitive technique for detecting focal lesions of the spleen than for detecting focal hepatic lesions.     

A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

Segmental intestinal muscular thinning: a possible cause of intestinal obstruction in the newborn

Intestinal obstruction proximal to a transition zone without an interposed physical barrier usually indicates Hirschsprung disease. The authors report one case of focal small bowel muscular thinning just distal to a transition zone that produced clinical and radiographic findings that simulated long-segment Hirschsprung disease in a 2-day-old infant.     

Development of hatching blastocysts from immature human oocytes following in-vitro maturation and fertilization using a co-culture system

Recently, in-vitro maturation (IVM) of immature human oocytes recovered from non-stimulated follicles has been applied in the treatment of infertility. However, in previous reports, very few embryos cultured in conventional medium have reached the expanded blastocyst stage following in-vitro maturation and fertilization (IVM/IVF). The objective of this study was to investigate whether the developmental competence of human embryos following IVM/IVF could be enhanced by the use of a human ampullary cell co-culture system. Immature human oocytes were aspirated from small follicles at Caesarean section and then cultured in medium containing human menopausal gonadotrophin for 36 to 48 h, followed by insemination. Zygotes were randomly cultured either in conventional culture medium alone or in the co-culture system. Of 48 embryos cultured in conventional medium alone, all arrested at the 2-16- cell stage on day 3 after insemination. Of 46 embryos cultured in the co-culture system, 26 embryos (56.5%) arrested at the 2-16-cell stage. Six embryos (13%) developed to the morula stage. Fourteen embryos (30.4%) developed to expanded blastocysts and two blastocysts were hatching on day 7 after insemination. We conclude that co-culture significantly enhances the development of blastocysts in embryos resulting from IVM/IVF.