Renal amyloidosis in a child with chronic granulomatous disease and invasive aspergillosis

A boy who had been diagnosed with chronic granulomatous disease (CGD) at the age of 6.5 years had a medical history of multiple bacterial infections, including pneumonia, staphylococcal liver abscesses and septicemia, from birth. At the age of 10 years and 4 months he developed an infection that was accompanied by high fever and pulmonary, mediastinal and paravertebral infiltrations. Aspergillus niger was cultured on bronchial secretions obtained by bronchoscopy. Shortly thereafter, proteinuria manifested and progressed to the nephrotic level. A skin biopsy indicated a diagnosis of amyloidosis. An anti-fungal treatment with amphotericin B and other agents, along with surgical pus drainage, intravenous leukocyte mass, interferon-γ and immunoglobulin infusions, was ineffective, and the patient eventually died from multi-organ failure. The postmortem examination revealed the presence of disseminated aspergillosis and systemic amyloidosis. Although no direct evidence is available that would confirm the causative role of aspergillosis in the development of systemic amyloidosis, to the best of our knowledge this is the first report of a CGD case with complications of both invasive aspergillosis and systemic amyloidosis.     

Correction to: Health-economic evaluation of home telemonitoring for COPD in Germany: evidence from a large population-based cohort

The European Journal of Health Economics - In the original article, the observation period for a small share of the control group was misspecified and led to increased hospital costs and increased...     

A novel approach for targeted elimination of CSPG4‐positive triple‐negative breast cancer cells using a MAP tau‐based fusion protein

Chondroitin sulfate proteoglycan 4 (CSPG4) has been identified as a highly promising target antigen for immunotherapy of triple‐negative breast cancer (TNBC). TNBC represents a highly aggressive heterogeneous group of tumors lacking expression of estrogen, progesterone and human epidermal growth factor receptor 2. TNBC is particularly prevalent among young premenopausal women. No suitable targeted therapies are currently available and therefore, novel agents for the targeted elimination of TNBC are urgently needed. Here, we present a novel cytolytic fusion protein (CFP), designated αCSPG4(scFv)‐MAP, that consists of a high affinity CSPG4‐specific single‐chain antibody fragment (scFv) genetically fused to a functionally enhanced form of the human microtubule‐associated protein (MAP) tau. Our data indicate that αCSPG4(scFv)‐MAP efficiently targets CSPG4⁺ TNBC‐derived cell lines MDA‐MB‐231 and Hs 578T and potently inhibits their growth with IC₅₀ values of ～200 nM. Treatment with αCSPG(scFv)‐MAP resulted in induction of the mitochondrial stress pathway by activation of caspase‐9 as well as endonuclease G translocation to the nucleus, while induction of the caspase‐3 apoptosis pathway was not detectable. Importantly, in vivo studies in mice bearing human breast cancer xenografts revealed efficient targeting to and accumulation of αCSPG4(scFv)‐MAP at tumor sites resulting in prominent tumor regression. Taken together, this preclinical proof of concept study confirms the potential clinical value of αCSPG4(scFv)‐MAP as a novel targeted approach for the elimination of CSPG4‐positive TNBC.     

Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and {varepsilon}-aminocaproic acid

The influence of the arachidonic acid metabolism inhibitors,indomethacin and voltaren; an inhibitor of phosphodiester-aseactivity, theophylline and the protease inhibitor -aminocaproicacid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacentalcarcinogenesis was studied in rats. ENU was given to pregnantrats as a single i.v. exposure at a dose of 75 mg/kg body weighton the 21st day after conception. Indomethacin and voltaren(20 p.p.m. in drinking water), theophylline (0.01% in diet)and EACA (1000 p.p.m. in drinking water) were given to the offspringthroughout their post-natal life until all survivors were killedat 12 months. In the ENU-only control groups, 100% of the offspringdeveloped tumors of brain, spinal cord, peripheral nervous systemor kidneys, with a total average number of 3.1 tumors per ratThe most marked inhibitory effect was exerted by theophylline,which significantly decreased the incidence and multiplicityof total tumors, and at all main sites selectively (brain, spinalcord, peripheral nerves and kidneys). It also prolonged averagesurvival time of the offspring. Indomethacin and voltaren significantlydecreased total tumor incidence and multiplicity, and braintumor incidence and multiplicity. Indomethacin also decreasedkidney tumor multiplicity and voltaren diminished spinal cordtumor multiplicity. EACA decreased multiplicities of total,brain, peripheral nerve and kidney tumors, and diminished theincidence of brain tumors. These chemopreventive agents decreasedtumor incidences 20–33% and tumor multiplicities 1.4–2.7times, compared with the ENU-only controls.     

Preparation of highly specific radioactivity [18F]flumazenil and its evaluation in cynomolgus monkey by positron emission tomography

A straightforward method for the preparation of no-carrier-added (n.c.a.) [18F]flumazenil via standard nucleophilic radiofluorination of the corresponding nitro-analog Ro 15-2344 has been developed. The labeling was performed by employing the K18F/kryptofix complex in DMF at 160 degrees C for 30 min and equimolar ratio [K/K2.2.2]+18F-/precursor. Under these conditions, an 18F incorporation rate into flumazenil was in the range of 55-60%. The final product was isolated by HPLC purification within a total synthesis time of 75 min and a radiochemical yield of about 30% (EOB). Human post-mortem whole-hemisphere autoradiography of brain sections demonstrated selective uptake of the radioligand in the areas of high density of the central benzodiazepine receptors (BZR). PET studies in a cynomolgus monkey and metabolite studies by HPLC demonstrated similar results by [18F]flumazenil as for [11C]flumazenil. In blocking experiments, almost all radioactivity was inhibited by the addition of unlabeled flumazenil. [18F]Flumazenil is a suitable radioligand for PET assessment of the BZR.     

Cancer incidence in Arkhangelskaja Oblast in northwestern Russia. The Arkhangelsk Cancer Registry

Background

Data concerning incidence and prevalence of cancer in the different regions of Russia have traditionally not been provided on a basis that facilitated comparison with data from countries in western parts of Europe. The oncological hospital in Arkhangelsk, in co-operation with Universitetet i Tromsø (Norway), has established a population based cancer registry for Arkhangelskaja Oblast (AO). AO is an administrative unit with 1.3 million inhabitants in northwestern Russia. The aim of this investigation was to assess the content and quality of the AO cancer registry (AKR), and to present the site-specific cancer-incidence rates in AO in the period 1993–2001.

Methods

The population in this study consisted of all individuals registered as residents of AO. All new cancer cases in the period 1993 – 2001, registered the AKR, were included in the study (ICD-10: C00-C95, except for C77-78). The annual gender and age-group-specific population figures were obtained from the AO statistics office.

Results

A total of 34 697 cases of primary cancers were included. The age-adjusted (world standard) incidence rate for all sites combined was 164/100 000 for women and 281/100 000 for men. The highest incidence was for cancer of the trachea, bronchus and lung (16.3% of all cases), whereof 88.6 % of the cases were among men. Among women, cancer of the breast constituted 15.9 percent of all cases. The age-adjusted incidences of the most frequent cancer sites among men were: lung (77.4/100 000); stomach (45.9); rectum (13.4); oesophagus (13.0); colon (12.2); bladder (11.6); and prostate cancer (11.1). Among women they were: breast (28.5); stomach (19.7); colon (12.2); and ovary cancer (9.0).

Conclusion

Our findings confirm and strengthen the indication that the incidences of stomach, larynx, liver, pancreas, prostate, colon, bladder and melanoma cancer are quite different in male populations in Russia compared to many other European countries. Among women, most major cancer types, except stomach, appear to be relatively low in Russian populations. The AKR provides quality data for estimations and insight to the cancer incidence in a northern Russian population, and we consider the reported incidence rates to reflect the cancer situation in AO well.

     

Cost-Utility Analysis Comparing Heavy-Weight and Light-Weight Mesh in Laparoscopic Surgery for Unilateral Inguinal Hernias

Background

Hernioplasty is one of the most frequent surgeries in the UK. Light-weight mesh (LWM) has the potential to reduce chronic groin pain but its cost-effectiveness compared with heavy-weight mesh (HWM) is unknown.

Objective

Our objective was to conduct a cost-utility analysis between laparoscopic hernioplasty with HWM and LWM for unilateral inguinal hernias.

Methods

A Markov model simulated costs and health outcomes over a period of 1 year (2012) from the societal and National Health Service (NHS) perspective (England). The main outcome was cost per quality-adjusted life-year (QALY) gained. Surgery results were gleaned from the randomized control trial by Bittner et al. Other input parameters were drawn from the literature and public sources of the NHS.

Results

From the societal perspective, LWM induces lower incremental costs (?£88.85) than HWM but yields a slightly smaller incremental effect (?0.00094 QALYs). The deterministic incremental cost-effectiveness ratio (ICER) for HWM compared with LWM amounts to £94,899 per QALY, while the probabilistic ICER is £118,750 (95 % confidence interval [CI] £57,603–180,920). Owing to the withdrawal of productivity losses from the NHS perspective, LWM causes higher incremental costs (£13.09) and an inferior incremental effect (?0.00093), resulting in a dominance of HWM over LWM (ICER 95 % CI ?£12,382 to ?£21,590).

Conclusions

There is no support for the adoption of LWM as standard treatment from an NHS perspective. However, given the small differences between HWM and LWM, LWM has at least the potential of improving patient outcomes and reducing expenditure from the societal perspective.     

Who is to blame? Oxytocin promotes nonpersonalistic attributions in response to a trust betrayal

Recent research revealed that the neuropeptide Oxytocin (OT) increases and maintains trustful behavior, even towards interaction partners that have proven to be untrustworthy. However, the cognitive mechanisms behind this effect are unclear. In the present paper, we propose that OT might boost trust through the link between angry rumination and the use of nonpersonalistic and personalistic attributions. Nonpersonalistic attributions put the blame for the betrayal on the perpetrator's situation, whereas personalistic attributions blame his dispositions for the event. We predict that OT changes attribution processes in favor of nonpersonalistic ones and thereby boosts subsequent trust. Participants played a classic trust game in which the opponent systematically betrayed their trust. As predicted, OT strengthened the relationship between angry rumination about the event and nonpersonalistic attribution of the opponents’ behavior and weakened the link between angry rumination and personalistic attribution. Critically, nonpersonalistic attribution also mediated the interactive effect of OT and angry rumination on how strongly investments were reduced in the remaining rounds of the trust game. In summary, the present findings suggest that one underlying cognitive mechanism behind OT-induced trust might relate to how negative emotions evoked by a breach of trust influence the subsequent attributional analysis: OT seems to augment trust by fostering the interpretation of untrustworthy behavior as caused by non-personal factors.