Alport syndrome: impact of digenic inheritance in patients management.

Alport syndrome (ATS) is a genetically heterogeneous nephropathy with considerable phenotypic variability and different transmission patterns, including monogenic (X-linked/autosomal) and digenic inheritance (DI). Here we present a new series of families with DI and we discuss the consequences for genetic counseling and risk assessment. Out of five families harboring variants in more than one COL4 gene detected by next generation sequencing (NGS), minigene-splicing assay allowed us to identify four as true digenic. Two families showed COL4A3/A4 mutations in cis, mimicking an autosomal dominant inheritance with a more severe phenotype and one showed COL4A3/A4 mutations in trans, mimicking an autosomal recessive inheritance with a less severe phenotype. In a fourth family, a de novo mutation (COL4A5) combined with an inherited mutation (COL4A3) triggered a more severe phenotype. A fifth family, predicted digenic on the basis of silico tools, rather showed monogenic X-linked inheritance due to a hypomorphic mutation, in accordance with a milder phenotype. In conclusion, this study highlights the impact of DI in ATS and explains the associated atypical presentations. More complex inheritance should be therefore considered when reviewing prognosis and recurrence risks. On the other side, these findings emphasize the importance to accompany NGS with splicing assays in order to avoid erroneous identification of at risk members.

Distal femoral medial closing wedge osteotomy for degenerative valgus knee : mid-term results in active patients.

Distal femoral medial closing wedge osteotomy (DFMCWO) may be a valuable treatment for arthritic valgus knees in young and active adults, with the possible aim of procrastinating knee replacement. 32 valgus knees (mean age : 41.4±11.2) treated with DFMCWO were retrospectively reviewed. All the knees had a lateral compartment osteoarthritis graded I-II-III according to Kellgren Lawrence classification. 20 knees had osteochondral lesions, treated with microfractures (8) or bone marrow derived cells transplantation (12). Patients were clinically (IKDC, KOOS, NRS, Tegner) and radiologically evaluated. A mean follow-up of 62.12±15.65 was achieved. KOOS score peaked at 24 months, showed a decremental trend, achieved a final results of 79,59±17,14. Similar trend was evident for IKDC. The final NRS score was 2.73±1.82 ; the final Tegner score was 4.81±1.56. Radiographs showed degenerative progression in 5 knees : 2 patients underwent knee replacement at the final follow-up. DFMCWO is an effective treatment to treat osteoarthritic symptomatology, delay degenerative progression and avoid knee replacement in valgus knees at mid-term follow-up.

Compositional determinants of mechanical properties of enamel.

Dental enamel is comprised primarily of carbonated apatite, with less than 1% w/w organic matter and 4-5% w/w water. To determine the influence of each component on the microhardness and fracture toughness of rat incisor enamel, we mechanically tested specimens in which water and organic matrix were selectively removed. Tests were performed in mid-sagittal and transverse orientations to assess the effect of the structural organization on enamel micromechanical properties. While removal of organic matrix resulted in up to a 23% increase in microhardness, and as much as a 46% decrease in fracture toughness, water had a significantly lesser effect on these properties. Moreover, removal of organic matrix dramatically weakened the dentino-enamel junction (DEJ). Analysis of our data also showed that the structural organization of enamel affects its micromechanical properties. We anticipate that these findings will help guide the development of bio-inspired nanostructured materials for mineralized tissue repair and regeneration.

Bone marrow transplantation in a thalassemia patient with congenital heart disease.

We report a thalassemia patient suffering from congenital transposition of the great arteries, surgically corrected according to Mustard technique at the age of 4 months, who underwent bone marrow transplantation. Despite a syncopal episode occurring during the first day after marrow infusion the transplant was successful. Thirty-two months later, normalization of hematologic parameters was observed together with a substantial improvement in cardiac function.

Cardiac tamponade in thalassemia.

We report a case of acute cardiac tamponade without concurrent myocardial disease occurring in a thalassemia patient early after bone marrow transplantation. The pericardial effusion was preceded by an episode of junctional tachycardia. Repeated evaluation by echocardiography was done shortly after the patient developed the arrhythmia and permitted a detailed, timed observation of the event and description of the symptoms.

A versatile mechanical ventilator (DIGIT) with high flow stability and a programmable inspiratory phase flow pattern.

The paper describes the general characteristics of a newly developed nonconstant-flow generator for automatic ventilation of the lungs. It is known that the application of very high pressure to high internal resistance leads to a very stable flow, in that the flow itself is unaffected by external load (patient) variations. The stability of the flow means that the inspiratory process can be controlled by means of the ventilated volume, thus extending DIGIT utilization to high resistance patients. The modulation of the flow is implemented via a digital electromechanical system, which allows the ventilator functions to be accurately programmed. The desired flow waveform is obtained by means of a series of pneumatic valves, the apertures of which are digitally controlled. The design is innovative in that it allows the flow waveform in each of the ten digitalized time steps into which each inspiratory phase is divided to be both programmed and controlled. Other ventilators commercially available and currently in use do not have this functional capability, as they are all designed to model the integral flow of the inspiratory waveform without being able to modify the subunit time steps of a single inspiratory phase. The paper also discusses the results of fundamental tests concerning the performance characteristics of the ventilator.

[An information survey on the automatic operation of intensive therapy units in Italy]. / Indagine conoscitiva sulla gestione automatica delle sale di terapia intensiva in Italia.

A fact finding study was carried out in 58 resuscitation centres and 78 intensive care units to evaluate the current application of computerised techniques in the monitoring and processing of various parameters relating to hospitalised patients. The enquiry revealed a marked interest in the use of computerised systems, particularly in the electrophysiological and haemodynamic field. Promising results were reported from some centres. Some adverse criticisms and points of discussion still exist. International and national experiences matured so far, however, while primarily directed towards scientific research and technological development, open up significant perspectives for the future, for the rational handling of the data collected, and the extension of current knowledge on matters of physiopathology, electrophysiology, and pharmacokinetics.

Nano hydroxyapatite-coated implants improve bone nanomechanical properties.

Nanostructure modification of dental implants has long been sought as a means to improve osseointegration through enhanced biomimicry of host structures. Several methods have been proposed and demonstrated for creating nanotopographic features; here we describe a nanoscale hydroxyapatite (HA)-coated implant surface and hypothesize that it will hasten osseointegration and improve its quality relative to that of non-coated implants. Twenty threaded titanium alloy implants, half prepared with a stable HA nanoparticle surface and half grit-blasted, acid-etched, and heat-treated (HT), were inserted into rabbit femurs. Pre-operatively, the implants were morphologically and topographically characterized. After 3 weeks of healing, the samples were retrieved for histomorphometry. The nanomechanical properties of the surrounding bone were evaluated by nanoindentation. While both implants revealed similar bone-to-implant contact, the nanoindentation demonstrated that the tissue quality was significantly enhanced around the HA-coated implants, validating the postulated hypothesis.

Needle liver biopsy in thalassaemia: analyses of diagnostic accuracy and safety in 1184 consecutive biopsies.

We report the reliability and safety of percutaneous liver biopsy in the evaluation of hepatic iron loading and histology in patients with homozygous beta-thalassaemia prior to and in serial biopsies following allogeneic bone marrow transplantation for this disorder. 501 thalassaemic patients aged 11 +/- 4.5 years (range 1-32 years) underwent 1184 consecutive percutaneous liver biopsies without ultrasound guidance. Overall, 81% of biopsies were evaluable for histological examination and grading of iron. The adequacy of liver biopsy specimens increased with patient age: evaluable specimens were obtained in 73% of patients < 5 years of age and in 86% of samples in patients aged > 15 years. The degree of iron overload and fibrosis in each biopsy was reported separately by at least two pathologists who did not know the clinical status of each patient. In 103 biopsies, iron grade by light microscopy corresponded to an iron concentration varying between a mean of 32.46 +/- 14 mumol/g dry weight liver tissue for iron stores graded by light microscopy as absent to 417.6 +/- 150 mumol/g dry weight liver tissue for stores graded as severe. The fibrosis score of multiple samples of liver obtained at autopsy within 100 d of the percutaneous biopsy in 41 patients who died following BMT correlated perfectly with that of the first sample in > 60% biopsies; in most of the discordant cases fibrosis had been underestimated in the percutaneous biopsy. Liver biopsy demonstrated evidence of chronic hepatitis in 30% of patients with normal transaminase and in 57% of patients with transaminase within twice the normal range. Liver biopsy was complicated in six patients (0.5%) by haemoperitoneum, periocholecystic haematoma, kidney haematoma, or bile peritonitis; no complication was fatal. These data demonstrate that percutaneous liver biopsy provides reliable information regarding liver iron and histology in homozygous beta-thalassaemia with an extremely low risk of complications.