Mutational and biochemical findings in adults with persistent hypophosphatasemia.

A majority of adults with persistently low serum alkaline phosphatase values carry a pathogenic or likely pathogenic variant in the ALPL gene and also have elevated alkaline phosphatase substrate values in serum and urine. These adults may fall within the spectrum of the adult form of hypophosphatasia. INTRODUCTION: The primary objective of this study was to determine what proportion of adults with persistently low serum alkaline phosphatase values (hypophosphatasemia) harbor mutations in the ALPL gene or have elevated alkaline phosphatase (ALP) substrates. Some adults with persistent hypophosphatasemia share clinical and radiographic features with the adult form of hypophosphatasia (HPP). In HPP, ALPL mutations result in persistent hypophosphatasemia and ALP substrate accumulation in plasma (pyridoxal-5-phosphate (PLP)) and urine (phosphoethanolamine (PEA)). METHODS: Biochemical analyses, including serum ALP activity, bone-specific ALP, plasma PLP, and urine PEA, were performed in adults with persistent hypophosphatasemia. Mutational analyses were performed using PCR and Sanger sequencing methods. Gene variants were classified as pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). P and LP variants were further grouped as "Positive ALPL variants" and LB and B grouped as "Negative ALPL variants." RESULTS: Fifty subjects completed all mutational and biochemical analyses. Sixteen percent carried only Negative ALPL variants. Of the remaining 42 subjects, 67% were heterozygous for a P variant, 19% for an LP variant, and 14% for a VUS. Biochemical results were highly inter-correlated and consistent with the expected inverse relationship between ALP and its substrates. Subjects harboring Positive ALPL variants showed lower ALP and BSAP and higher PLP and PEA values compared with subjects harboring only Negative ALPL variants. Approximately half of all subjects harboring Positive ALPL variants or ALPL VUS showed elevations in plasma PLP, and three quarters showed elevations in urine PEA. CONCLUSION: Adults with persistent hypophosphatasemia frequently harbor ALPL mutations and have elevated ALP substrates. These adults may fall within the spectrum of the adult form of hypophosphatasia. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present.

Ex vivo perfusion of the swine heart as a method for pre-transplant assessment.

We describe a cost-effective, reproducible circuit in a porcine, ex vivo, continuous warm-blood, bi-ventricular, working heart model that has future possibilities for pre-transplant assessment of marginal hearts donated from brain stem dead donors and hearts donated after circulatory determination of death (DCDD). In five consecutive experiments over five days, pressure volume loops were performed. During working mode, the left ventricular end systolic pressure volume relationship (LV ESPVR) was 23.1±11.1 mmHg/ml and the LV preload recruitable stroke work (PRSW) was 67.8±7.2. (Standard PVAN analysis software) (Millar Instruments, Houston, TX, USA) All five hearts were perfused for 219±64 minutes and regained normal cardiac function on the perfusion system.They displayed a significant upward and leftward shift of the end systolic pressure volume relationship, a significant increase in preload recruitable stroke work and minimal stiffness. These hearts could potentially be considered for transplantation. The circuit was effective during reperfusion and working modes whilst proving to be successful in maintaining cardiac function in excess of four hours. Using an autologous prime of approximately 20% haematocrit (Hct), electrolytes and blood gases were easy to control within this period using standard perfusion techniques.

Stimulant use and the potential for abuse in Wisconsin as reported by school administrators and longitudinally followed children.

The purpose of this study was to describe stimulant use and abuse as reported by school administrators and children diagnosed with attention deficit/hyperactivity disorder or attention deficit disorder inattentive. Five years after being identified as Ritalin responders, 161 children were surveyed regarding stimulant use and abuse. School principals in central Wisconsin were also surveyed regarding stimulant use and policies. No child believed stimulants as prescribed could lead to abuse. Sixteen percent of the children had been approached to sell, give, or trade their medication. During school hours, 44% of children and 37% of schools reported stimulants were stored unlocked. Not all schools had written policies regarding prescription drugs, and 10% permitted students to carry their own medication. Monitoring prescription usage, periodic reassessment of efficacy, and continuing education of family and teaching staff should be part of the multimodal treatment for this disorder. School policies should be developmentally sensitive.

[Assessment of respiratory physiology signals in very low-weight newborn infant with respiratory deficiency]. / Untersuchungen über die Auswertbarkeit atemphysiologischer Messsignale bei atemgestörten, sehr untergewichtigen Neugeborenen.

1. Lung function tests in newborn babies breathing spontaneously were performed commonly using a pneumotachometer to measure the tidal volume and an esophageal catheter to measure the transpulmonary pressure changes. 2. The quality of the measured signals depends on the breath-to-breath variability of the signals as well as on the frequency of different artifacts and disturbances due to physiological interferences. 3. The evaluation of the signals in very low birth weight infants with respiratory distress is often difficult due to the irregular pattern of respiration, the reduced signal-noise-ratio and the high number of artifacts. 4. The subjective assessment of the quality of 115 records of respiratory signals has shown that 54% of all records can be evaluated easily, in 40.8% the evaluation was difficult and in 5.2% an evaluation was not possible. 5. The qualitative analysis of respiratory signals shows that in this age group the computer-aided signal evaluation requires a new view in the detection and elimination of artifacts as well as in the calculation of characteristic results from a sufficient number of evaluated breathing cycles.