Formulation and Clinical Evaluation of Sodium Benzoate Oral Solution for the Treatment of Urea Cycle Disorders in Pediatric Patients.

BACKGROUND: Sodium benzoate, a common food preservative, is used in the treatment of patients with urea cycle disorders (UCDs) as it stimulates ammonia removal by a non-urea cycle-based pathway. Despite its use in the clinical routine, no commercially available oral formulations currently exist. Liquid formulation is normally well accepted in pediatric age and allows precise dosage according to the children's needs. AIMS: (1) To prepare an oral sodium benzoate solution in different tastes and determine its stability, palatability, and tolerability and (2) to describe the long-term follow-up of two pediatric patients with UCDs treated with our formulation. METHODS: We prepared five oral solutions of sodium benzoate (200 mg/ml) by adding different flavoring agents. We measured drug concentration in the samples by high-performance liquid chromatography (HPLC). We evaluated palatability and tolerability with adult volunteers. Long-term drug compliance and metabolic control were appraised in two pediatric patients. RESULTS: All the oral solutions remained stable at room temperature along the 96-day test period, and they were well tolerated. The mint-flavored solution resulted the most palatable and preferred by adult volunteers. We report good drug compliance and good metabolic outcomes for both pediatric patients during the entire follow-up. CONCLUSIONS: Our study highlighted the stability and tolerability of flavored sodium benzoate oral solutions. These solutions were well accepted during a long-term follow-up and guaranteed a good metabolic control. Since taste attributes are critical to ensure acceptable medication adherence in the pediatric age, flavored liquid formulations of sodium benzoate may be an efficient strategy to achieve therapeutic outcomes in UCD pediatric patients.

Colonic content in health and its relation to functional gut symptoms.

BACKGROUND: Gut content may be determinant in the generation of digestive symptoms, particularly in patients with impaired gut function and hypersensitivity. Since the relation of intraluminal gas to symptoms is only partial, we hypothesized that non-gaseous component may play a decisive role. METHODS: Abdominal computed tomography scans were evaluated in healthy subjects during fasting and after a meal (n = 15) and in patients with functional gut disorders during basal conditions (when they were feeling well) and during an episode of abdominal distension (n = 15). Colonic content and distribution were measured by an original analysis program. KEY RESULTS: In healthy subjects both gaseous (87 ± 24 mL) and non-gaseous colonic content (714 ± 34 mL) were uniformly distributed along the colon. In the early postprandial period gas volume increased (by 46 ± 23 mL), but non-gaseous content did not, although a partial caudad displacement from the descending to the pelvic colon was observed. No differences in colonic content were detected between patients and healthy subjects. Symptoms were associated with discrete increments in gas volume. However, no consistent differences in non-gaseous content were detected in patients between asymptomatic periods and during episodes of abdominal distension. CONCLUSIONS & INFERENCES: In patients with functional gut disorders, abdominal distension is not related to changes in non-gaseous colonic content. Hence, other factors, such as intestinal hypersensitivity and poor tolerance of small increases in luminal gas may be involved.

Intestinal gas content and distribution in health and in patients with functional gut symptoms.

BACKGROUND: The precise relation of intestinal gas to symptoms, particularly abdominal bloating and distension remains incompletely elucidated. Our aim was to define the normal values of intestinal gas volume and distribution and to identify abnormalities in relation to functional-type symptoms. METHODS: Abdominal computed tomography scans were evaluated in healthy subjects (n = 37) and in patients in three conditions: basal (when they were feeling well; n = 88), during an episode of abdominal distension (n = 82) and after a challenge diet (n = 24). Intestinal gas content and distribution were measured by an original analysis program. Identification of patients outside the normal range was performed by machine learning techniques (one-class classifier). Results are expressed as median (IQR) or mean ± SE, as appropriate. KEY RESULTS: In healthy subjects the gut contained 95 (71, 141) mL gas distributed along the entire lumen. No differences were detected between patients studied under asymptomatic basal conditions and healthy subjects. However, either during a spontaneous bloating episode or once challenged with a flatulogenic diet, luminal gas was found to be increased and/or abnormally distributed in about one-fourth of the patients. These patients detected outside the normal range by the classifier exhibited a significantly greater number of abnormal features than those within the normal range (3.7 ± 0.4 vs 0.4 ± 0.1; p < 0.001). CONCLUSIONS & INFERENCES: The analysis of a large cohort of subjects using original techniques provides unique and heretofore unavailable information on the volume and distribution of intestinal gas in normal conditions and in relation to functional gastrointestinal symptoms.

Mechanisms of abdominal distension in severe intestinal dysmotility: abdomino-thoracic response to gut retention.

BACKGROUND: We previously showed that abdominal distension in patients with functional gut disorders is due to a paradoxical diaphragmatic contraction without major increment in intraabdominal volume. Our aim was to characterize the pattern of gas retention and the abdomino-thoracic mechanics associated with abdominal distension in patients with intestinal dysmotility. METHODS: In 15 patients with manometrically proven intestinal dysmotility, two abdominal CT scans were performed: one during basal conditions and other during an episode of severe abdominal distension. In 15 gender- and age-matched healthy controls, a basal scan was performed. KEY RESULTS: In basal conditions, patients exhibited more abdominal gas than healthy subjects, particularly in the small bowel, and the volume significantly increased during an episode of distension. During episodes of abdominal distension, the increase in abdominal content was associated with increased girth and antero-posterior abdominal diameter, as well as a cephalic displacement of the diaphragm, which reduced the height of the lung. The consequent reduction in the air volume of the lung was attenuated by an increase in the antero-posterior diameter of the chest. CONCLUSIONS & INFERENCES: Abdominal distension in patients with severe intestinal dysfunction is related to marked pooling of gut contents, particularly in the small bowel. This increase in content is accommodated within the abdominal cavity by a global and coordinated abdomino-phreno-thoracic response, involving an accommodative ascent of the diaphragm and a compensatory expansion of the chest wall.

Abdominal accommodation induced by meal ingestion: differential responses to gastric and colonic volume loads.

BACKGROUND: Using an experimental model of colonic gas infusion, we previously showed that the abdominal walls adapt to its content by an active phenomenon of abdominal accommodation. We now hypothesized that abdominal accommodation is a physiological phenomenon, and aimed to confirm that it can be induced by ingestion of a meal; a secondary aim was to determine whether the response to gut filling is region-specific. METHODS: In healthy subjects (n = 24) a nutrient test meal was administered until tolerated at a rate of 50 mL min(-1). Electromyographic (EMG) activity of the anterior wall (upper and lower rectus, external and internal oblique) was measured via four pairs of surface electrodes, and EMG activity of the diaphragm via intraluminal electrodes on an esophageal tube. To address the secondary aim, the response to gastric filling was compared with that induced by colonic filling (1440 mL 30 min(-1) anal gas infusion; n = 8). KEY RESULTS: Participants tolerated 927 ± 66 mL of meal (450-1500 mL). Meal ingestion induced progressive diaphragmatic relaxation (EMG reduction by 16 ± 2%; P < 0.01) and selective contraction of the upper abdominal wall (24 ± 2% increase in activity of the upper rectus and external oblique; P < 0.01 for both), with no significant changes in the lower rectus (4 ± 2%) or internal oblique (5 ± 3%). Colonic gas infusion induced a similar response, but with an overall contraction of the anterior wall. CONCLUSIONS & INFERENCES: Meal ingestion induces a metered and region-specific response of the abdominal walls to accommodate the volume load. Abnormal abdominal accommodation could be involved in postprandial bloating.

B-type natriuretic peptide in the evaluation and management of dyspnoea in primary care.

OBJECTIVES: The rapid and accurate diagnosis of heart failure in primary care is a major unmet clinical need. We evaluated the additional use of B-type natriuretic peptide (BNP) levels. DESIGN: A randomized controlled trial. SETTING: Twenty-nine primary care physicians in Switzerland and Germany coordinated by the University Hospital Basel, Switzerland. SUBJECTS: A total of 323 consecutive patients presenting with dyspnoea. INTERVENTIONS: Assignment in a 1 : 1 ratio to a diagnostic strategy including point-of-care measurement of BNP (n = 163) or standard assessment without BNP (n = 160). The total medical cost at 3 months was the primary end-point. Secondary end-points were diagnostic certainty, time to appropriate therapy, functional capacity, hospitalization and mortality. The final diagnosis was adjudicated by a physician blinded to the BNP levels. RESULTS: Heart failure was the final diagnosis in 34% of patients. The number of hospitalizations, functional status and total medical cost at 3 months [median $1655, interquartile range (IQR), 850-3331 vs. $1541, IQR 859-2827; P = 0.68] were similar in both groups. BNP increased diagnostic certainty as defined by the need for further diagnostic work-up (33% vs. 45%; P = 0.02) and accelerated the initiation of the appropriate treatment (13 days vs. 25 days; P = 0.01). The area under the receiver-operating characteristics curve for BNP to identify heart failure was 0.87 (95% confidence interval, 0.81-0.93). CONCLUSIONS: The use of BNP levels in primary care did not reduce total medical cost, but improved some of the secondary end-points including diagnostic certainty and time to initiation of appropriate treatment.

Accommodation of the abdomen to its content: integrated abdomino-thoracic response.

BACKGROUND: We previously showed that changes in intra-abdominal content induce a volume-dependent muscular response of the anterior abdominal wall and the diaphragm. We aimed to determine the contribution of the thorax to abdominal accommodation and the influence of the intra-abdominal expansion rate. METHODS: Gas (1440 mL total load) was infused into the colon of nine healthy subjects, while abdomino-thoracic perimeters (by tape measure), electromyography (EMG) activity of the diaphragm (via six ring electrodes over an esophageal tube in the hiatus), intercostals and anterior abdominal wall (via five pairs of surface electrodes) and the position of the diaphragm by ultrasonography were measured. Infusion rates of 24, 48, and 96 mL min(-1) were tested on separate days. KEY RESULTS: Gas infusion induced anterior abdominal wall contraction (18 ± 1% EMG increment; P < 0.001) with relatively modest girth increment (4.9 ± 0.9 mm; P = 0.001), diaphragmatic relaxation (by 15 ± 1%; P < 0.001) with cephalad displacement (by 23 ± 6 mm; P = 0.005), and intercostal contraction (by 19 ± 2%; P < 0.001) with increased thoracic perimeter (by 2.0 ± 0.5 mm; P = 0.009). Responses were similar with the three infusion rates. CONCLUSIONS & INFERENCES: Accommodation of intra-abdominal loads involves a volume-related integrated abdomino-thoracic response regardless of the expansion rate.

Collecting close-contact social mixing data with contact diaries: reporting errors and biases.

The analysis of contact networks plays a major role to understanding the dynamics of disease spread. Empirical contact data is often collected using contact diaries. Such studies rely on self-reported perceptions of contacts, and arrangements for validation are usually not made. Our study was based on a complete network study design that allowed for the analysis of reporting accuracy in contact diary studies. We collected contact data of the employees of three research groups over a period of 1 work week. We found that more than one third of all reported contacts were only reported by one out of the two involved contact partners. Non-reporting is most frequent in cases of short, non-intense contact. We estimated that the probability of forgetting a contact of ≤5 min duration is greater than 50%. Furthermore, the number of forgotten contacts appears to be proportional to the total number of contacts.

[Hyperprolactinemia in a man's world]. / Hyperprolaktinämie - in a man's world.

A 60-years old patient was admitted for mamillary pain for several weeks, without galactorrhea. Erectile dysfunction had been present for several years but diminished libido had developed only recently. Ultrasonography of the mamillary gland was not definite for gynecomastia but repeated serum prolactin concentrations were elevated 5-fold the upper limit of normal. Furthermore serum level of testosterone was decreased and levels of luteinizing hormone and follicle-stimulation hormone were within normal range. Magnetic resonance imaging (MRI) of the pituitary gland could not identify a tumoral mass. In review of the laboratory features and the absence of a tumoral mass on MRI, idiopathic hyperprolactinemia was diagnosed and therapy with a dopamine-agonist was started.

[Early gastric cancer--or not]. / Magenfrühkarzinom oder doch nicht?

A 46-year old female patient presented with non-specific epigastric discomfort that had been present for 6 months. Endoscopic work-up showed a small gastric polyp and biopsy samples revealed adenocarcinoma. There was no evidence of metastatic disease or penetration of the muscle layer on endosonography, rating the tumor as early gastric cancer. Endoscopic submucosal dissection was unsuccessful due to bleeding complications and the patient was treated with subtotal gastrectomy. Surprisingly, the final histological diagnosis revealed a highly differentiated neuroendocrine tumor and the initial diagnosis had to be revised.

[Non-controllable blood pressure peaks--pheochromocytoma?]. / Nicht kontrollierbare Blutdruckspitzen--Phäochromozytom?

A 59-year old patient presented with a history of arterial hypertension, refractory to combined antihypertensive treatment with ACE-inhibitors, diuretics, calcium channel blockers and beta blockers. Blood pressure values ranged from 180/100mmHg to 90mmHg systolic after medication intake. Diagnostic work-up revealed renal artery stenosis on duplexsonography that was treated by percutaneous transluminal angioplasty and stent implantation. After the intervention, blood pressure values remained normal even without antihypertensive treatment.

[Malnutrition in hospitals--a pilot study]. / Mangelernährung im Spital--Eine pilotstudie.

RATIONALE: Malnutrition in hospitals is often not assessed and malnourished patients rarely receive specific nutritional therapy. METHODS: 50 consecutive patients were assessed using the Nutritional Risk Score (NRS). 22 patients (intervention group, IG) with > or = 3 points were treated with 3 daily servings of a high-protein, high-caloric supplement. 28 patients (non-intervention-group, NIG) with < 3 points received standard hospital food. Body weight, body-mass-index (BMI) and laboratory values were obtained at admission and discharge. The amount of calorie and protein intake was compared to daily requirements. RESULTS: Median duration of hospital stay was longer in the IG (24 d vs. 13 d, p < 0.01) and duration raised with the number of points in the NRS. Patients in the IG only had decreased albumin values (-2.9 g/l, p < 0.01), whereas patients in the NIG showed loss of body weight (-1.3 kg, p < 0.01), BMI (-0.45 kg/m2, p < 0.01) and albumin values (-2.4 g/l, p <0.01) during their stay. Transferrin levels remained unchanged. Median daily intake of calories and proteins was similar in both groups. In the IG, the percentage of required calorie (94% vs. 79%, p < 0.01) and protein (80% vs. 68%, p < 0.01) intake was higher and the number of patients with intake of < 75% of estimated calorie (7 (32%) vs. 11 (39%), p = 0.01) and protein (13 (59%) vs. 22 (79%), p = 0.04) requirements was lower. CONCLUSIONS: Patients in the IG were more likely to maintain their nutritional status although their hospital stay was significantly longer.

[28-year old patient with successfully treated dilatative cardiomyopathy]. / 28-jähriger Patient mit erfolgreich behandelter dilatativer Kardiomyopathie.

A 28-year was admitted with heart failure. His medical history included treatment for hypogonadotropic hypogonadism. Echocardiography showed dilatation of all chambers. Elevated serum ferritin levels and liver biopsy indicated hereditary hemochromatosis. Cardiac iron overload was seen on magnetic resonance imaging. Genetic testing revealed homozygosis for G320 V mutation, confirming the diagnosis of juvenile hemochromatosis. Phlebotomy on a biweekly regimen was started and after twelve months of therapy the patient had normal ferritin values as well as normal ejection fraction on echocardiography.

[Subtherapeutic blood levels of phenytoin due to a medication error]. / Subtherapeutische Phenytoinspiegel infolge eines Medikationsfehlers.

We report a female patient who was admitted to the emergency ward with suspected cerebral ischemia and in whom transvenous clot lysis was performed. Following lysis the patient developed recurrent complex partial seizures and treatment with intravenous phenytoin was started. Initial phenytoin serum levels were within the therapeutic range. During the course of the in-hospital treatment a sudden fall of phenytoin serum levels was detected and could not be explained by pharmacokinetic changes. Only when the drug application process was further analysed the reason for the fall in serum levels became obvious. Phenytoin sodium injections had not been administered directly into the veins but had been diluted in 0.9% saline infusions. As a result phenytoin sodium injections precipitated and were retained by the particle filter, thus leading to subtherapeutic phenytoin serum levels.

[Mycobacterium avium pneumonia in an HIV negative patient]. / Mycobacterium-avium-Pneumonie bei HIV-negativem Patienten.

A 79-year-old patient was admitted with fever and shortness of breath. His medical history included treatment for lung cancer 3 years previously. The patient's clinical and radiological status remained unchanged despite antibiotic treatment for pneumonia. No infectious pathogen could be identified. Treatment with systemic steroids for suspected cryptogenic organizing pneumonitis (COP) was started. Following steroid treatment the patient's shortness of breath ameliorated and C-reactive protein was normal. Three weeks after admission Mycobacterium avium complex (MAC) grew in sputa cultures and therefore a diagnosis of MAC pneumonia was made.

Pulmonary vein thrombosis after lower lobectomy of the left lung.

Pulmonary vein thrombosis is a known complication after lung transplantation but has rarely been reported after lobectomy or bilobectomy. We report the case of a left upper pulmonary vein thrombosis following an uneventful left lower lobectomy for bronchial carcinoma. Postoperative arterial blood gas values and chest radiographs were normal. On postoperative day 5, the patient became progressively dyspneic, developed hemoptysis and showed total opacification of the left lung without mediastinal shift on chest radiography. The patient remained dyspneic despite intravenous antibiotic therapy for suspected pneumonia and absence of obstruction at bronchoscopy. Diagnosis of left upper pulmonary vein thrombosis was finally made by contrast-enhanced multislice computed tomography followed by pulmonary angiography. Further clinical deterioration under conservative treatment forced us to remove the remnant left upper lobe that already showed gangrenous alterations. Pulmonary vein thrombosis following lobectomy or bilobectomy is very rare. Only 7 cases have been reported in the literature so far. Conservative treatment with antibiotics and anticoagulants may be successful but in case of clinical deterioration the affected lobe has to be resected. The mechanism of thrombosis remains unclear although intraoperative torsion and injury of vessels seem to be most likely since pulmonary vein thrombosis occurred in the operated hemithorax only.

[Fever, malaise and new onset mitral valve insufficiency. Subacute Streptococcus bovis mitral valve endocarditis ]. / Fieber, Leistungsknick und neu aufgetretene Mitralinsuffizienz. Subakute Mitralklappen-Endocarditis mitStreptococcus bovis.

A 62-year-old patient with low grade fever, fatigue, arthralgia and newly discovered mitral regurgitation was diagnosed with subacute endocarditis. Streptococcus bovis grew from all six blood culture bottles. Streptococcus bovis is known to be associated with gastrointestinal neoplasias. Therefore a colonoscopy was performed and two polyps were removed. Histological analysis revealed a tubulovillous adenoma and a serrated adenoma. Colonoscopy is mandatory for all patients with Streptococcus bovis endocarditis even without any symptoms for colorectal neoplasia. The significance of Streptococcus bovis for the carcinogenesis of colorectal neoplasias and the possible alternative pathway for colorectal carcinomas through serrated adenomas will be discussed.