Refining the dermatological spectrum in primary immunodeficiency: mucosa-associated lymphoid tissue lymphoma translocation protein 1 deficiency mimicking Netherton/Omenn syndromes.

The proteinase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which forms part of the caspase recruitment domain-containing protein 11-B-cell lymphoma 10-MALT1 signalosome complex, plays a direct role in nuclear factor kappa B activation. Here, we describe the case of a female infant with severe immune dysregulation leading to recurrent systemic infections, failure to thrive and severe crises of ichthyosiform erythroderma with high levels of serum IgE. Hence, initial symptoms indicated Netherton syndrome or Omenn syndrome. Surprisingly, sequence analyses of SPINK5 and RAG1/RAG2, respectively, excluded these diseases. During the hospital stay the patient's health deteriorated, despite intensive care therapy, and she died. In order to delineate the diagnosis, whole-exome sequencing was performed. Two compound heterozygous mutations in MALT1 were found and verified by Sanger sequencing (exon 2 c.245T>C, exon 2 c.310dup), which led to a MALT1 deficiency at the protein level. Based on these results, an immunological analysis was performed, as was immunofluorescence staining of key skin proteins, to confirm a diagnosis of MALT1 deficiency. This case report provides a closer description of the clinical and histological skin phenotype of MALT1 deficiency, and we conclude that MALT1 deficiency must be considered a possible differential diagnosis of Netherton and Omenn syndromes. What's already known about this topic? Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) deficiency is a combined immunodeficiency. MALT1 is part of the caspase recruitment domain-containing protein 11-B-cell lymphoma 10-MALT1 signalosome complex, which is essential for nuclear factor kappa B activation. Current publications describe a phenotype of recurrent systemic infections; only in a few cases has an inflammatory involvement of the integument been described. What does this study add? A closer description of the cutaneous phenotype of MALT1 deficiency in a patient with two novel MALT1 mutations. Immune mapping of follicular epidermis shows lympho-epithelial Kazal-type-related inhibitor is reduced in MALT1 deficiency and absent on interfollicular staining. Clinically, MALT1 deficiency mimics Netherton syndrome and Omenn syndrome, and should be considered a differential diagnosis.

Selective prevention of mechanical hyperalgesia after incision by spinal ERK1/2 inhibition.

BACKGROUND: Activation of extracellular signal-regulated kinases (ERK1/2) has been shown to play an important role in several pain states. Here we investigated the ERK1/2 contribution to non-evoked and evoked pain-like behaviour in rats after surgical incision. METHODS: Spinal phosphorylation of ERK1 and ERK2 was assessed 15 min, 4 h, 24 h and 5 days after plantar incision and sham incision. The effect of PD98059, a specific inhibitor of ERK1/2 activation, administered intrathecally (IT) 1 h before or 2 h after incision on spinal ERK1 and ERK2 phosphorylation was assessed. In behavioural experiments, the effect of PD98059 administered 1 h before or after incision on non-evoked pain behaviour and mechanical and heat hyperalgesia was assessed. RESULTS: Phosphorylated ERK1 and ERK2 were rapidly increased in the ipsilateral dorsal horn from rats after incision post-operatively. This increased ERK1 and ERK2 phosphorylation were blocked by PD98059 administered before incision. In congruence, IT administration of PD98059 before incision delayed mechanical hyperalgesia after incision; however, administration after incision had only a modest effect on mechanical hyperalgesia. In addition, PD98059 did not affect non-evoked pain behaviour or heat hyperalgesia after incision. CONCLUSION: The results suggest that spinal ERK1 and ERK2 are involved in regulation of pain after incision differentially with regard to the pain modality. Furthermore, blockade of ERK1/2 activation was most effective in a preventive manner, a condition which is rare after incision. Spinal ERK1/2 inhibition could therefore be a very useful tool to manage selectively movement-evoked pain after surgery in the future.

Anesthetic management in pediatric patients with epidermolysis bullosa: a single center experience.

BACKGROUND: Anesthesia in children with dystrophic epidermolysis bullosa (EB) presents a significant challenge as many children have a difficult airway and are at risk for additional blistering. In this retrospective study we compared deep sedation/ analgesia and general anesthesia for safety and efficiency. Procedure, type of anesthesia, airway management, complications, time for induction and awakening, length of stay in recovery room, length of procedure were noted and compared, qualitatively and with statistic tests as appropriate. METHODS: Fourteen children underwent 148 procedures: 79 under general anesthesia, 67 under sedation. RESULTS: Several complications - including intubation difficulties and the need for change of airway management - were observed in the general anesthesia group, none in the sedated group. Induction time was 36 min vs. 17 min (P<0.001), mean time to recovery 23 min vs. 6 min (P<0.001). Surgical duration did not differ between groups. CONCLUSIONS: In children with dystrophic EB deep sedation/ analgesia can be safely performed and is less time consuming than traditional management.

Non-return valves do not prevent backflow and bacterial contamination of intravenous infusions.

Non-return valves (NRVs) are designed to avoid backflow of infusion fluid against the designated direction of flow (DDF) when more than one infusion is delivered via one venous access. We tested in vitro whether NRVs reliably prevent flow against the DDF at clinically relevant low flow rates. Since catheter-related infections caused by the infusion of contaminated fluids represent a relevant problem in patient care, we tested whether NRVs preclude bacterial contamination of infusions proximal to the NRVs and thus might play a role in preventing healthcare-associated infections. Additionally, the incidence of bacterial contamination of drips and infusion fluids in our intensive care unit (ICU) was quantified. In vitro, a low flow against the DDF of ten examples each of five different NRV models was applied and the integrity for fluid and transmigration of three different indicator micro-organisms was tested. Second, we investigated whether contamination of intravenous infusion tubing collected from patients treated on our ICU occurred. Largely independent from the model, 40% of the tested NRVs were not leak-tight for fluids when a pressure against the DDF was built up slowly. In 30%, bacteria migrated against the DDF and were detected proximal to the valve. In 6.7% of the tubing samples collected from ICU patients we detected bacterial contamination. In conclusion, contamination of drips is a relevant problem on ICU. NRVs neither reliably prevent backflow of fluids nor serve as micro-organism filters. Therefore they cannot be recommended as a way of reducing healthcare-associated infections.

[Glycemic control in sepsis and septic shock: friend or foe?]. / Blutzuckerkontrolle bei Patienten mit Sepsis und septischem Schock: Freund oder Feind?

INTRODUCTION: Intensive care patients commonly suffer from hyperglycemia. Evidence is growing that strictly maintaining normoglycemia by intensive insulin therapy (IIT) ameliorates outcome in these patients. Whether or not this also holds true for patients with sepsis and septic shock is the issue of this post-hoc analysis of the database (2,748 patients) of 2 recent prospective clinical trials. MATERIAL AND METHODS: A total of 950 patients suffering from sepsis were identified and of these 462 fulfilled the diagnostic criteria of septic shock upon admission to the intensive care unit (ICU). Patients were treated by either IIT [mean glycemia 5.88 mmol/l (106 mg/dl)] or conventional glucose management [mean glycemia 8.44 mmol/l (152 mg/dl)]. RESULTS: Under IIT the mortality of patients treated for more than 3 days in the ICU was lowered by 7.6% (p=0.03) in septic patients and by 8.7% (p=0.08) in septic shock patients. Polyneuropathy occurred less frequently under IIT compared to conventional glucose management (sepsis -9.8%, septic shock -14%; p<0.001). The incidence of acute renal failure was not affected by either treatment regimen (sepsis -3.3%, septic shock -3.1%; p<0.25). Intensive insulin therapy was associated with an increased risk of hypoglycemia (sepsis +16.7%, septic shock +18.8; p<0.0001) which did not, however, directly affect morbidity nor mortality. CONCLUSIONS: These data suggest that IIT improves outcome of patients with sepsis or septic shock. Hypoglycemia is a frequent complication, but its clinical relevance remains to be defined.