Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.

BackgroundHereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients.MethodsClinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected.ResultsKey features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes.ConclusionsHFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.

Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.Ceftaroline is a novel broad-spectrum cephalosporin with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) strains due to its strong affinity for S. aureus penicillin-binding proteins (PBPs), including PBP 2A, the additional protein responsible for the methicillin resistance mechanism (6, 15). Ceftaroline acetate (PPI-0903) is an Nphosphono water-soluble prodrug rapidly metabolized in vivo into the bioactive metabolite ceftaroline . No study has been performed by using a challenging rabbit infection model of experimental endocarditis, which has proved to be highly valuable in evaluating the in vivo effectiveness of antibiotics. The aim of the present study was to evaluate the in vivo activity of ceftaroline compared with those of other antistaphylococcal drugs by using a rabbit model of aortic valve endocarditis with doses projected to be therapeutic for humans.We studied two MRSA strains isolated from blood cultures. The MRSA strain (originally designated SA-2) was a strain with heterogeneous high-level methicillin resistance (methicillin MIC ϭ 128 mg/liter) (7), and the heterogeneous glycopeptide-intermediate S. aureus strain (hGISA) exhibited homogeneous resistance to methicillin (methicillin MIC Ͼ 1,024 mg/ liter) and heterogeneous resistance to glycopeptides (8). The MICs were determined in cation-supplemented Mueller-Hinton broth by the microdilution technique (1, 11). Bactericidal activity was assessed on the basis of the determination of minimal bactericidal concentrations (MBCs) by the microdilution method and on the basis of the results of time-kill experiments with an inoculum of 5 ϫ 10 6 CFU/ml (12). High-performance liquid chromatography was used to determine the concentrations of linezolid (13) (lower detection limit, 0.1 mg/liter; coefficient of variation, Ͻ10%). Assays with vancomycin were performed by an immunoenzymatic method with a COBAS MIRA unit and EMIT reagents (Behring Diagnostics Inc., Cupertino, CA) (detection threshold, 2.5 mg/ liter; coefficient of variation, 4.1 to 6.9%). Active ceftaroline concentrations were determined by a microbiologic assay with Bacillus subtilis as the test organism and antibiotic medium 2 (Difco Laboratories, Detroit, MI) as the diffusion medium (lower detection limit, 0.25 mg/liter; intraday and interday variations, Ͻ10%). Simulation of the pharmacokinetics of linezolid was performed as validated previously (7). For ceftaroline, blood samples were taken from six healthy rabbits after administration of a ceftaroline acetate bolus of 10 and 30 mg/kg of body weight in order to determine the spontaneous drug ...

Spontaneous haemorrhage associated with chronic pancreatitis in 17 patients was related to a pseudocyst in 15 (88 per cent) patients and to pancreatic lithiasis (one patient) or to infarction-rupture of the spleen (one patient). Bleeding was massive in six patients and intermittent in 11. It resulted from erosion of the gastroduodenal or the splenic artery in four patients. Bleeding into the pancreatic duct occurred in four patients and erosion of the duodenum by a bleeding pseudocyst in five. Haemorrhage was confined to a pseudocyst in six patients and was intraperitoneal in two. Of the 15 patients with bleeding pseudocysts, ten underwent primary pancreatic resection (eight proximal and two distal pancreatectomies) with no mortality but four had early complications. Four of the five patients who underwent transcystic ligation of bleeding vessels and pseudocyst drainage had postoperative complications: one died from sepsis and liver failure and three underwent reoperation for severe postoperative bleeding. Of these, two had proximal pancreatic resection with one death. The third patient had further suture ligation and external drainage. The overall postoperative mortality rate was 12 per cent and following emergency surgery 33 per cent. Favourable results were achieved in two-thirds of patients when the primary operative strategy could be directed towards the control of bleeding and removal of the affected pancreatic segment. Primary pancreatic resection, although technically demanding in the presence of haemorrhage, is recommended whenever possible for the treatment of bleeding pancreatic pseudocysts and pseudoaneurysms associated with chronic pancreatitis.

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