Hepatocellular Adenoma in a Patient with Ornithine Transcarbamylase Deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked recessive disorder that leads to hyperammonemia and liver damage. Hepatocellular adenoma in OTC deficiency patients has not been previously described. Here we report the first such case to be described in the English language scientific literature.

Ethical considerations of population screening for late-onset genetic disease.

Population-based genetic screening has been a mainstay of public health in the United States for many years. The goal of genetic screening is to identify individuals at increased risk for treatable diseases. The evolution of genetic testing to include multi-disease panels allows for new screening applications which challenge the traditional model of clinical genetics care by the identification of late-onset disorders in an asymptomatic fetus, child, or adult. We present two unique examples of individuals referred to a biochemical genetics clinic due to the detection of late-onset Pompe disease by population-based screening modalities. We review early experiences in counseling and management of pre-symptomatic individuals and highlight some of the primary ethical factors warranting consideration as we enter the era of genomic medicine.

Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.

UNLABELLED: We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). STUDY DESIGN: These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. RESULTS: Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. CONCLUSION: The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.

Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate.

UNLABELLED: Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). STUDY DESIGN: Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. RESULTS: Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 µmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p≥0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. CONCLUSIONS: These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.

Mycoplasma testudineum sp. nov., from a desert tortoise (Gopherus agassizii) with upper respiratory tract disease.

Mycoplasma testudineum sp. nov., first cultured from the upper respiratory tract of a clinically ill tortoise (Gopherus agassizii) in the Mohave Desert, was distinguished from previously described mollicutes serologically and by 16S rRNA gene sequence comparisons. It lacks a cell wall; ferments glucose, mannose, lactose and sucrose; does not produce 'film and spots'; does not hydrolyse arginine, aesculin or urea; is sensitive to digitonin; and lacks phosphatase activity. The organism causes chronic rhinitis and conjunctivitis of tortoises. The type strain of M. testudineum is BH29T (= ATCC 700618T = MCCM 03231T).

Expression of cholera toxin B subunit oligomers in transgenic potato plants.

A gene encoding the cholera toxin B subunit protein (CTB), fused to an endoplasmic reticulum (ER) retention signal (SEKDEL) was inserted adjacent to the bi-directional mannopine synthase P2 promoter in a plant expression vector containing a bacterial luciferase AB fusion gene (luxF) linked to the P1 promoter. Potato leaf explants were transformed by Agrobacterium tumefaciens carrying the vector and kanamycin-resistant plants were regenerated. The CTB-SEKDEL fusion gene was identified in the genomic DNA of bioluminescent plants by polymerase chain reaction amplification. Immunoblot analysis indicated that plant-derived CTB protein was antigenically indistinguishable from bacterial CTB protein, and that oligomeric CTB molecules (M(r) approximately 50 kDa) were the dominant molecular species isolated from transgenic potato leaf and tuber tissues. Similar to bacterial CTB, plant-synthesized CTB dissociated into monomers (M(r) approximately 15 kDa) during heat or acid treatment. The maximum amount of CTB protein detected in auxin-induced transgenic potato leaf and tuber tissues was approximately 0.3% of total soluble plant protein. Enzyme-linked immunosorbent assay methods indicated that plant-synthesized CTB protein bound specifically to GM1-ganglioside, the natural membrane receptor of cholera toxin. In the presence of the SEKDEL signal, CTB protein accumulates in potato tissues and is assembled into an oligomeric form that retains native biochemical and immunological properties. The expression of oligomeric CTB protein with immunological and biochemical properties identical to native CTB protein in edible plants opens the way for preparation of inexpensive food plant-based oral vaccines for protection against cholera and other pathogens in endemic areas throughout the world.

Don't forget the serratus.

Patients quadriplegic at the C6 level may not be considered candidates for independent transfers and weight shifting because of lack of primary shoulder depressors. However, we have observed that some quadriplegics have been able to use the serratus anterior for this latissimus dorsi function. We present an example of this technique, demonstrated by a patient with a complete C6 injury, and compare him with a subject with normal musculature.

Incidence of lumbar disc surgery. A population-based study in Olmsted County, Minnesota, 1950-1979.

Age- and sex-specific incidence rates of operation for suspected lumbar disc prolapse were determined for residents of Olmsted County, Minnesota, for the 30-year period 1950 through 1979. The incidence rate (adjusted to the age and sex distribution of the United States white population in 1980) was 52.3 per 100,000 person-years for all such operations and 46.3 per 100,000 person-years for initial operations. These rates remained fairly constant over the study period. A distinction was made between surgically proven and unproven cases of lumbar disc prolapse. Patients with a surgically proven lumbar disc prolapse had about 10 times the risk of another operation for disc prolapse within 10 years after the first operation compared with the general population.

Advances in orthotics for the patient with rheumatoid arthritis.

Orthotics are externally applied devices which support a joint or enhance its function. In arthritis orthotics are prescribed to stabilize joints, provide better positioning, reduce pain, prevent deformity and improve function. Splints are used primarily for the upper extremity. Specially designed shoes can control foot and ankle pain and instability. Continuous passive motion devices are becoming widely used for early postoperative rehabilitation after arthroplasty. Unfortunately, few controlled studies have been performed to determine the utility of orthoses in patients with arthritis. Some of the most important questions on this subject are posed and available data discussed as well as the need for additional information.

Renal function in spinal cord injury: a preliminary report.

To investigate the effect of current bladder management techniques on renal function in spinal cord injury (SCI), we followed 99 patients by frequent examinations, excretory urograms, and iothalamate short renal clearances. Fifty-eight percent of the subjects emptied their bladders by catheter-free methods (bladder retrained), 32% by intermittent self-catheterization, and 10% by indwelling urethral catheters. All remained clinically well, but more and earlier excretory urogram abnormalities occurred in the intermittent self-catheterization group. Twenty-one percent of the intermittent self-catheterization group but only 5% of the bladder retrained group had excretory urogram abnormalities. Declines of more than 10% in short renal clearance values were noted in 30% of intermittent self-catheterization patients and in 15% of bladder retrained patients. Our preliminary data support the need for close surveillance and follow-up after SCI rehabilitation, even in patients appearing clinically well. These data also suggest that renal function can be preserved with current bladder management methods, with bladder retraining having a slight edge over intermittent self-catheterization.

Measurement of trunk flexibility in normal subjects: reproducibility of three clinical methods.

Although measurements of trunk flexibility are an important part of a clinical examination, subjective methods are usually used to assess spinal mobility. We studied three easily performed objective techniques for determining trunk flexibility (the common "fingertip-to-floor" test, the modified Schober and Moll tests, and the Loebl inclinometer method) and their interexaminer and intraexaminer reproducibility. On 3 different days, each of 25 normal subjects was tested by the same investigator. In 25 other subjects, the studies were performed by a different examiner (one of three) on each of 3 days. We recorded the following mean coefficients of variation for interexaminer and intraexaminer reproducibility of results, respectively: fingertip-to-floor, 83% and 76.4%; flexion (Schober), 6.3% and 6.6%; right lateral flexion (Moll), 11.9% and 8.9%; left lateral flexion (Moll), 10.2% and 9.5%; extension (Moll), 9.5% and 7.3%; lumbar flexion (Loebl), 9.6% and 13.4%; and lumbar extension (Loebl), 65.4% and 50.7%. Although the reproducibility of the "fingertip-to-floor" test and the Loebl extension test was poor, all other tests studied had good reproducibility. The consistency of results with repeated testing should be considered in the application of various trunk flexibility tests to clinical and research data.

Energy expenditure in patients with low-, mid-, or high-thoracic paraplegia using Scott-Craig knee-ankle-foot orthoses.

Renewed interest in ambulation in patients with paraplegia prompted us to measure the energy expenditure (kcal/kg per min) during standing and ambulating with the Scott-Craig orthosis in nine patients who had low-, mid-, or high-thoracic paraplegia. Energy expenditure during standing and during ambulation with a walker was similar for patients with all levels of paraplegia. In patients with high-thoracic paraplegia, energy efficiency was significantly less (P less than 0.05) than that for patients with mid- or low-thoracic paraplegia, whose efficiency levels were similar. In patients with low-thoracic paraplegia, the only patients who could perform swing-through gait patterns, energy efficiency was increased because of increased velocity. Our data do not support the concept of denying, on the basis of the level of the lesion alone, young, otherwise healthy, well-motivated patients with thoracic paraplegia the opportunity of using Scott-Craig orthoses to supplement wheelchair mobility and activities of daily living.

Paraplegic energy expenditure during negotiation of architectural barriers.

Long-leg braces are often used by persons with paraplegia to negotiate architectural barriers, and thereby increase their wheelchair mobility. Such barriers include ramps, stairways, and narrow corridors requiring multiple turns. This study was designed to measure the energy expenditure during such activities for two long-leg orthoses: standard braces without a dorsiflexion stop and Scott-Craig braces. Energy expenditure was measured in eight subjects by indirect spirometry using Douglas bag collection and Haldane analysis. Data obtained were used to calculate oxygen consumption per minute, volume of oxygen per turn, step, or meter, and calories per minute during each activity. Using Scott-Craig braces on one day and standard braces on another day, each subject negotiated five 90 degrees turns and two 180 degree turns, ten 15.24 cm steps, both up and down, and an 11.9 m ramp inclined 12 degrees, both up and down. Milliliters of oxygen consumed per kilogram of body weight per turn, step, or meter were recorded for Scott-Craig braces, standard braces, and normal walking. All of these activities required a high expenditure of energy. No significant difference was apparent between the standard and the Scott-Craig braces for any activity.

Methenamine mandelate with acidification: an effective urinary antiseptic in patients with neurogenic bladder.

We studied the effectiveness of methenamine mandelate in preventing urinary tract infection in patients with neurogenic bladder dysfunction who were in a program of intermittent catheterization and bladder retraining. Nine of 17 patients (53%) became infected while receiving the drug, whereas 19 of 22 patients (86%) in a placebo group became infected during the trial. The difference in infection rates was statistically significant (P less than 0.02) and resulted primarily from the absence of gram-positive cocci and Pseudomonas species in the drug group.

Effect of traumatic spinal cord transection on human upper gastrointestinal motility and gastric emptying.

Whether transection of the spinal cord, above the level of the sympathetic outflow to the gastrointestinal tract, alters human upper gastrointestinal function is yet unknown. In 5 patients with complete high-cord transection (neurologic level above T1), 3 patients with complete low-cord transections (neurologic level T10 or below), and 4 age- and sex-matched healthy controls, the duration of the phases and cycle length of the interdigestive motor complex were similar. However, the percentage of phase III's of the interdigestive motor complex that originated in the antrum and propagated to the duodenum was significantly decreased in patients with high-cord transections compared with healthy subjects (38% vs. 90%; p less than 0.05), but was similar in patients with low-cord transections and normal controls (75% vs. 90%). After liquid meals, 3 of the 3 high-cord patients tested had reduced cumulative gastric emptying at 60 min postprandially compared with healthy subjects. Thus, interruption of the cervical cord above the level of the sympathetic outflow to the gastrointestinal tract disturbs normal interdigestive antral-duodenal motor coordination and may delay postprandial gastric emptying of liquid meals.

Videogame adaptation for patients with high-level cervical injury.

Any device that will help improve the quality of life for the patient with high-level cervical injury should be of interest to rehabilitation workers. A new option in this area, not yet widely appreciated or exploited, is the home videogame system. We describe certain modifications needed to adapt such games to the use of cervical injury patients.

Energy expenditure of paraplegic patients standing and walking with two knee-ankle-foot orthoses.

To determine which kind of knee-ankle-foot orthosis (KAFO) is more efficient, we measured energy expenditure in standing, walking with a walker, and walking with crutches by eight subjects using the Scott-Craig KAFO and a single-stopped long-leg KAFO. All subjects had complete motor paralysis below the level of their lesion and had been fully trained to use KAFOs. Every subject used both types of KAFO, and energy expenditure--per minute and per meter traveled--was measured by oxygen consumption. No significant difference in energy expenditure appeared during standing. During ambulation, however, mean energy expenditure was less with the Scott-Craig KAFO than with the single-stopped type: 31% less kcal/m with a walker and 25% less kcal/min with crutches. These results suggest that the Scott-Craig KAFO is more energy-efficient than the single-stopped long-leg KAFO.