Clinical,immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.     

Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices

Brain ischemia is frequently associated with oxidative stress in the reperfusion period. It is known that noradrenaline (NA) is released in excess under energy deprivation by the sodium-dependent reversal of the monoamine carrier. However, it is not known how oxidative stress affects NA release in the brain alone or in combination with energy deprivation. As a model of oxidative stress, the effect of H(2)O(2) (0.1-1.5 mM) perfusion was investigated in superfused rat hippocampal slices. It elicited a dose-dependent elevation of the release of [(3)H]NA and its tritiated metabolites as well as a simultaneous drop in the tissue energy charge. Mitochondrial inhibitors, i.e. rotenone (10 microM), and oligomycin (10 microM) in combination, also decreased the energy charge, but they had only a mild effect on [(3)H]NA release. However, when H(2)O(2) was added together with oligomycin and rotenone their effect on [(3)H]NA release was greatly exacerbated. H(2)O(2) and mitochondrial inhibitors also induced an increase in [Na(+)](i) in isolated nerve terminals, and their effect was additive. The effect of H(2)O(2) on tritium release was temperature-dependent. It was also attenuated by the glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (30 microM) and (+/-)-2-amino-5-phosphonopentanoic acid (10 microM), by the nitric oxide synthase inhibitors, N omega-nitro-L-arginine methyl ester (100 microM), or 7-nitroindazole (50 microM) and by the vesicular uptake inhibitor tetrabenazine (1 microM). Our results suggest that oxidative stress releases glutamate followed by activation of postsynaptic ionotropic glutamate receptors that trigger nitric oxide production and results in a flood of NA from cytoplasmic stores. The massive elevation of extracellular NA under conditions of oxidative stress combined with mitochondrial dysfunction may provide an additional source of highly reactive free radicals thus initiating a self-amplifying cycle leading to neuronal degeneration.     

Involvement of doctors in torture: conclusions and recommendations

In 1984 the Council of the British Medical Association set up a working party, chaired by J.P. Quillam, to investigate claims that doctors in some countries were cooperating with the use of torture as a routine instrument of repression. The conclusions and recommendations of the working party's recently published report are reproduced here, along with a list of the members of the working party. Among the report's conclusions [which are reproduced also in the British Medical Journal 1986 Mar 15; 292(6522): 781-782] are that doctors have a responsibility to support any practitioner who refuses to keep silent about abuses of human rights, to check for signs of physical abuse of prisoners, and to publicize any violations of the Declaration of Tokyo. Physicians are also encouraged to offer their services to organizations such as the Medical Foundation for the Care of Victims of Torture.     

The role of surgery in transmitting ≪ post-transfusion hepatitis ≫

The role of surgery as an additional risk in transmitting post-transfusion hepatitis was investigated in a retrospective study on acute hepatitis occurring in 77 transfused patients, 293 transfused and operated patients and 243 hepatitis cases with history of surgery without transfusion.Hepatitis A patients admitted to the same centres in the same period were utilized as controls. In transfused patients the percentage of NANB hepatitis was higher than that of type B (61.0% vs. 36.4%), while in the operated not transfused group the percentage of type B was twice that of type NANB (63.4% vs. 32.5%).In transfused and operated cases intermediate values were observed. The age-adjusted measures of association between exposures and the different hepatitis types showed a lack of effect of transfusion and a dominant role of surgery in transmitting type B hepatitis. In contrast, NANB post-transfusional cases were actually a mixture of post-transfusional and post-surgical cases, since both these exposures were found to be significantly associated with the disease.Our results suggest that studies on the incidence and the etiology of post-transfusion hepatitis should take into account the risk of surgical exposure which might have occurred.Corresponding author.     

The POSCH data processing experience

Metadata, the term, may be new but metadata, the concept, is not new. For purposes of this paper, the term metadata is defined as the data used to define, store, retrieve, combine, analyze, and present the data values (the “real” data, so to speak). As clinical research studies get larger, it becomes desirable to use automated managers of the metadata. The Program on the Surgical Control of the Hyperlipidemias (POSCH), a national multiclinic clinical trial, manages most of its metadata manually but has been experimenting with ways to more fully automate them. Its Information Management System (IMS) is described with special emphasis on how it manages the metadata. The case is presented for further automation and standardization of metadata in large clinical research studies so that costs can be contained and smaller increments of “progress” can be measured. The concept of a Metadatabase Management System (MDBMS) is developed and illustrated using POSCH.     

The Liver Retransplantation Risk Score: a prognostic model for survival after adult liver retransplantation

High-risk combinations of recipient and graft characteristics are poorly defined for liver retransplantation (reLT) in the current era. We aimed to develop a risk model for survival after reLT using data from the European Liver Transplantation Registry, followed by internal and external validation. From 2006 to 2016, 85 067 liver transplants were recorded, including 5581 reLTs (6.6%). The final model included seven predictors of graft survival: recipient age, model for end-stage liver disease score, indication for reLT, recipient hospitalization, time between primary liver transplantation and reLT, donor age, and cold ischemia time. By assigning points to each variable in proportion to their hazard ratio, a simplified risk score was created ranging 0–10. Low-risk (0–3), medium-risk (4–5), and high-risk (6–10) groups were identified with significantly different 5-year survival rates ranging 56.9% (95% CI 52.8–60.7%), 46.3% (95% CI 41.1–51.4%), and 32.1% (95% CI 23.5–41.0%), respectively (P < 0.001). External validation showed that the expected survival rates were closely aligned with the observed mortality probabilities. The Retransplantation Risk Score identifies high-risk combinations of recipient- and graft-related factors prognostic for long-term graft survival after reLT. This tool may serve as a guidance for clinical decision-making on liver acceptance for reLT.