The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype.

BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. CONCLUSIONS: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Immunohistochemical and biochemical evidence of ameloblastic origin of amyloid-producing odontogenic tumors in cats.

Amyloid-producing odontogenic tumors (APOT) are rare, and in cats, the histogenesis of the amyloid remains undetermined. In the present study, APOTs in 3 cats were characterized by immunohistochemistry, and the amyloid components analyzed using tandem mass spectrometry. Antiameloblastin antibodies labeled both neoplastic epithelial cells and amyloid in all cases. Neoplastic epithelial cells had strong, diffuse immunoreactivity to antibodies against cytokeratin AE1/AE3, cytokeratin 14, and cytokeratin 19 in all cases and focal immunoreactivity to nerve growth factor receptor antibodies in 2 of 3 cases. Amyloid and some tumor stromal cells were weakly positive for laminin. Calretinin, amelogenin, S100, and glial fibrillary acidic protein antibodies did not label neoplastic epithelial cells or amyloid. Extracted amyloid peptide sequences were compared to the porcine database because the cat genome is not yet complete. Based on this comparison, 1 identical ameloblastin peptide was detected in each tumor. These results suggest that feline APOTs and the amyloid they produce are of ameloblastic lineage.

[Cost analysis of telemedical treatment of stroke]. / Kostenanalyse telemedizinischer Schlaganfallbehandlung.

BACKGROUND: Telemedicine-enabled stroke networks increase the probability of a good clinical outcome. There is a shortage of evidence about the effects of this new approach on costs for inpatient care and nursing care. METHODS: We analysed health insurance and nursing care fund data of a statutory health insurance company (AOK Bayern). Data from stroke patients initially treated in a TeleStroke network (TEMPiS - telemedical project for integrative stroke care) between community hospitals and academic stroke centres were compared to data of matched hospitals without specialised stroke care and telemedical support. Costs for nursing care were obtained over a 30-month period after the initial stroke. To rule out pre-existing differences between network and control hospitals, costs of stroke care were also analysed during a time period before network implementation. FINDINGS: 1 277 patients (767 in intervention, 510 in control hospitals) were analysed in the post-implementation period. An increased proportion of patients treated in intervention hospitals had a favourable outcome concerning the level of required nursing care. Patients in intervention hospitals had higher costs for acute inpatient care (5 309 € vs. 4 901 €, p=0.04), but lower nursing care fund costs (3 946 € vs. 5 132 €; p=0.04). There was no difference in relation to absolute total costs obtained in the post-implementation period. However, nursing care costs per survived year were significantly lower in intervention hospitals (1 953 € vs. 2 635 €; p=0.005). No significant differences were found in the pre-implementation period. CONCLUSIONS: Considering both health insurance and nursing care fund costs, the incremental costs for TeleStroke network care in hospitals are compensated by savings in outpatient care.

Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I - A decade of experience.

The cerebral formation and entrapment of neurotoxic dicarboxylic metabolites (glutaryl-CoA, glutaric and 3-hydroxyglutaric acid) are considered to be important pathomechanisms of striatal injury in glutaric aciduria type I (GA-I). The quantitatively most important precursor of these metabolites is lysine. Recommended therapeutic interventions aim to reduce lysine oxidation (low lysine diet, emergency treatment to minimize catabolism) and to enhance physiologic detoxification of glutaryl-CoA via formation of glutarylcarnitine (carnitine supplementation). It has been recently shown in Gcdh(-/-) mice that cerebral lysine influx and oxidation can be modulated by arginine which competes with lysine for transport at the blood-brain barrier and the inner mitochondrial membrane [Sauer et al., Brain 134 (2011) 157-170]. Furthermore, short-term outcome of 12 children receiving arginine-fortified diet showed very promising results [Strauss et al., Mol. Genet. Metab. 104 (2011) 93-106]. Since lysine-free, arginine-fortified amino acid supplements (AAS) are commercially available and used in Germany for more than a decade, we evaluated the effect of arginine supplementation in a cohort of 34 neonatally diagnosed GA-I patients (median age, 7.43 years; cumulative follow-up period, 221.6 patient years) who received metabolic treatment according to a published guideline [Kölker et al., J. Inherit. Metab. Dis. 30 (2007) 5-22]. Patients used one of two AAS product lines during the first year of life, resulting in differences in arginine consumption [group 1 (Milupa Metabolics): mean=111 mg arginine/kg; group 2 (Nutricia): mean=145 mg arginine/kg; p<0.001]. However, in both groups the daily arginine intake was increased (mean, 137 mg/kg body weight) and the dietary lysine-to-arginine ratio was decreased (mean, 0.7) compared to infants receiving human milk and other natural foods only. All other dietary parameters were in the same range. Despite significantly different arginine intake, the plasma lysine-to-arginine ratio did not differ in both groups. Frequency of dystonia was low (group 1: 12.5%; group 2: 8%) compared with patients not being treated according to the guideline, and gross motor development was similar in both groups. In conclusion, the development of complementary dietary strategies exploiting transport competition between lysine and arginine for treatment of GA-I seems promising. More work is required to understand neuroprotective mechanisms of arginine, to develop dietary recommendations for arginine and to evaluate the usefulness of plasma monitoring for lysine and arginine levels as predictors of cerebral lysine influx.

[Indications and outcome of ventilated patients treated in a neurological intensive care unit]. / Indikationen und Outcome beatmeter Patienten einer neurologischen Intensivstation.

OBJECTIVE: This study characterized artificially ventilated patients in a neurological intensive care unit (NICU) between 2006-2008 in a purely neurological clinic and a so-called stand-alone situation. In addition the long-term prognoses as well as the quality of life of surviving patients were investigated. METHODS: All ventilated patients from October 2006 to December 2008 were enrolled in this descriptive, retrospective study. The duration of stay in intensive care was analyzed and the current quality of life was prospectively assessed based on the patient records. Final diagnoses, duration of intensive care unit and ventilation as well as the highest score in SAPS II (simplified acute physiology score) and complications during hospitalization were determined. The patients were divided into groups based on the diagnoses as vascular, inflammatory, neurodegenerative, hereditary, epileptogenic and others. Additionally patients were contacted and asked to respond by completing questionnaires on the Barthel index (BI) and the modified Rankin scale (mRS). RESULTS: During the study period a total of 512 patients were treated in the NICU of whom 201 required artificial respiration. Cerebrovascular diseases were the main reason for therapy in the NICU in 96 out of 201 cases (47.8%), followed by inflammatory diseases in 46 (22.8%) and epileptogenic diseases in 26 patients (13%). The median duration of artificial respiration was 9 days with a mean treatment duration of 16 days (range 1-57 days). Of the patients 31 (15.4%) died in the NICU and an additional 32 patients (18.8%) died within a median of 2 months after discharge. Outcome data were available from 67 out of 170 sent questionnaires and rehabilitation reports of 86 patients, which enabled the outcome of 121 surviving patients to be analyzed (71.2%). Of these 42.2% showed no or mild impairment in everyday life. However, the remaining 38% had severe impairments according to the BI. The evaluation of the mRS showed that 49.6% of the patients still had severe symptoms. CONCLUSIONS: More than one third of the patients treated in the NICU required artificial ventilation with an emphasis on cerebrovascular diseases, which illustrates the overlap between stroke unit and NICU care. Despite a lengthy duration of ventilation and a long stay in the intensive care unit more than one third of surviving patients showed no or only mild impairment. However, an additional third suffered from severe disability up to nursing care dependency. The study data differ little from the few publications in this field despite the stand alone situation of the NICU. The case mix index per day averaged around 0.3 and underlines the economic importance with respect to other forms of neurological treatment.

Leukoplakia and erythroplakia of the oral mucosa--a brief overview.

Leukoplakia and erythroplakia are the two most common potentially malignant disorders of the oral cavity. The prognosis and overall survival of a patient with oral cancer is dependent on the early detection of any lesion that might identify a patient with higher risk than normal or with early infiltration before metastatic disease. The role of the general dentist cannot be overstressed and the aim of this brief summary is to give the general practitioner an overview on the current concepts relating to these disorders. Leukoplakia and erythroplakia were traditionally known as two "precancerous lesions of the oral mucosa". The term "precancer" defines all lesions classified as such to have a "precancerous nature" implying that all of them will eventually become malignant. Through the years it became known that even clinically normal mucosa may show features of dysplasia and in some instances molecular aberrations of early malignant transformation may be found in the mucosa of a patient without any clinical lesions or dysplasia. The consensus view then was to introduce the term: "potentially malignant disorders" (PMD) reflecting the more generalised mucosal involvement in these patients. It remans a challenge to predict the behaviour of any of these lesions but early detection thereof remains the best chance any oral cancer patient will have for survival.

Use of guidelines improves the neurological outcome in glutaric aciduria type I.

OBJECTIVE: To evaluate the effect of treatment according to current evidence-based recommendations on the neurological outcome of patients with glutaric aciduria type I (GA-I). METHODS: Fifty-two patients identified by newborn screening (NBS) in Germany from 1999 to 2009 were followed prospectively. Neurological outcome was assessed by the occurrence of an acute encephalopathic crisis and the severity of a movement disorder (MD) with predominant dystonia superimposing on axial hypotonia. Outcome was evaluated in relation to therapy and therapy-independent parameters. RESULTS: Outcome was best in GA-I patients who were treated in full accordance with treatment recommendations (n=37; 5% MD). Deviations from recommended basic metabolic treatment (low-lysine diet, carnitine) resulted in an intermediate outcome (n=9; 44% MD), whereas disregard of emergency treatment recommendations was associated with a poor outcome (n=6; 100% MD). Treatment regimens deviating from recommendations significantly increased the risk for MD (odds ratio [OR], 35; 95% confidence interval [CI], 5.88-208.39) and acute encephalopathic crises (OR, 51.32; 95% CI, 2.65-993.49). Supervision by a metabolic center improved the outcome (18% vs 57% MD; OR, 6.17; 95% CI, 1.15-33.11), whereas migrational background and biochemical phenotype (high versus low excretor status) had no significant effect. INTERPRETATION: Follow-up of neonatally diagnosed patients with GA-I in Germany clearly demonstrates that the inclusion of this rare disease in the NBS disease panel has significantly improved the neurological outcome of affected individuals. The establishment of and adherence to evidence-based treatment recommendations, and supervision by experienced metabolic centers helps to minimize the number of patients who do not benefit from NBS.

Immunohistochemical profile of odontogenic epithelium in developing dog teeth (Canis familiaris).

Tumors of the jaw bones and oral soft tissue are relatively common lesions in dogs. The aim of this study was to find cell markers to differentiate odontogenic epithelium from nonodontogenic epithelium for future research on the pathogenesis and pathology of odontogenic neoplasms in dogs. Keratin 14 and 19 staining was observed in odontogenic and nonodontogenic epithelium, whereas amelogenin and p75 neurotrophin receptor immunoreactivity was observed in certain odontogenic epithelial cells at various stages of development but not in other epithelial cells. Calretinin staining was observed in the alveolar epithelial cells directly overlying the developing tooth germ in 28 of 39 sections (71.8%), as well as the dental laminae in 30 of 35 sections (85.7%) and Serres rests in 24 of 28 sections (85.7%). Focal positivity was detected in the respiratory mucosa, some hair follicles, and fusion epithelium of the palate, but no calretinin staining was observed in other oral epithelial cells; therefore, calretinin has potential to be utilized as a marker to differentiate odontogenic form nonodontogenic epithelium.

[Acceptance of telemedicine for acute stroke care. The German project TEMPiS]. / Akzeptanz der Telemedizin in der akuten Schlaganfallversorgung. Das bayerische Projekt TEMPiS.

BACKGROUND: Telemedicine is increasingly used for acute stroke care, making neurological expertise available in nonspecialized hospitals. There are few data about telemedicine's acceptance by either medical staff or patients at treating hospitals. METHODS: Telemedicine's acceptance was evaluated in the Telemedical Project for Integrative Stroke Care (TEMPIS), a network of two stroke centers and 12 community hospitals in the German state of Bavaria; the grading of teleconsultation regarding video and audio quality, time consumption, and medical relevance was assessed in two periods, 2004 and 2007. Overall satisfaction with in-hospital treatment was compared between patients in telemedically-linked hospitals with specialized stroke care and patients treated in conventional community hospitals. With regard to sufficient follow-up rates, ratings were restricted to patients living at home without severe disability at 3 months after stroke. A second evaluation analyzed how the parameter "Telemedical assessment of patient" (36% of patients in TEMPIS hospitals) affected overall satisfaction. RESULTS: Respectively, 140 and 127 uses of telemedicine were assessed in the two evaluation periods. Video quality, time consumption, and medical relevance were graded "excellent" by over 50% in both periods. Audio quality was rated "excellent" by only 22% in the first period but 69% in the second. Excellent overall satisfaction was expressed significantly more frequently by patients at TEMPIS hospitals (total number 1044) than by those at control hospitals (total number 484; 56% vs 47% respectively, P<0.01). Patient consultation via telemedicine per se did not correlate with modified grading. CONCLUSIONS: Acceptance of telemedicine in acute stroke care was high and stable over a long period. This study suggests improved overall satisfaction with treatment in hospitals offering specialized care and linked via telemedicine. Clinical assessment via telemedicine had no major effect on satisfaction.

[Botulinum toxin in the treatment of benign prostatic hyperplasia : an overview]. / Botulinumtoxin in der Therapie der benignen Prostatahyperplasie : Ein Uberblick.

The aim of this article is to provide a state-of-the-art review about the treatment of benign prostatic hyperplasia with botulinum toxin injections into the prostate. We searched PubMed for original articles until July 2007. Abstracts published at international congresses were also considered if they contributed substantial new information. Injections were performed mostly via the transperineal route under local anesthesia.From this review it appears that a majority of patients with benign prostatic hyperplasia experiences an improvement of both subjective parameters (IPSS, AUA symptom score) and objective parameters such as peak flow rate, postvoid residual volume, and prostate volume. An effect could be shown for different patient groups including different prostate sizes and different symptom characteristics. A high success rate and sustained duration of the effect of at least 12 months could be achieved. Side effects were marginal, and no systemic side effects were reported.Placebo-controlled studies with sufficient patient numbers and long-term follow-up are needed to determine the future value of this procedure in the treatment of patients with benign prostatic hyperplasia.

Estimating exposed pulp lengths of tusks in the African elephant (Loxodonta africana africana).

Captive and wild African elephants frequently suffer tusk fractures. Several institutions shorten the tusks of captive elephants to reduce fractures and injury as a result of behaviour within enclosures. Fracturing or coronal amputations that expose pulp lead to pain for the elephant. Estimating coronal pulp lengths may thus help to minimise the risk of pulp exposure during amputations. We aimed to determine the length of the pulp beyond the lip margin from an external tusk characteristic. Tusks collected from elephants in Namibia and the Kruger National Park had similar morphological relationships. This statistical property allowed us to correct for missing data in our data sets. Pulp volume and pulp length correlated with tusk circumference at the lip. Even so, the circumference at the lip could not predict the length of the pulp in the crown external to the lip. Our findings suggest that tusks, irrespective of sex or age, amputated further than 300 mm from the lip should not expose pulp.

Oral, Maxillofacial and Dental Diseases in Captive Cheetahs (Acinonyx jubatus).

Descriptions of several oral, maxillofacial and dental conditions/diseases exist for a variety of captive large felids, but little is reported on the pathology of free roaming large felids. Apart from focal palatine erosions (FPEs) as initially described by Fitch and Fagan (1982) and some reference to absent incisor teeth, few data exist on diseases affecting the oral, maxillofacial and dental structures of cheetahs (Acinonyx jubatus), regardless of their captivity status. This study reports 18 different conditions affecting the teeth, bone and oral cavity soft tissue of cheetahs, based on initial assessment of 256 animals over 11 years (2002-2012) in South Africa and Namibia. This report excludes oral tumours or FPEs, but includes several acquired and developmental conditions never described before.

Odontoma-like tumours of squirrel elodont incisors--elodontomas.

Since 2003, nine squirrels were presented at a South African veterinary dental practice with lesions in the maxilla consistent with the clinical, radiological and histological features of odontomas as described in prairie dogs, rats and mice. These odontoma-like masses have not previously been described in squirrels. This report describes the clinico-pathological features and possible pathogenesis of the lesions and proposes the term "elodontoma" for these hamartomatous odontogenic lesions in the jaws of animals with continuously erupting (elodont) teeth.

In vitro comparison of three materials as apical sealants of equine premolar and molar teeth.

REASONS FOR PERFORMING STUDY: Surgical endodontic therapy is a conservative dental technique used in horses with some degree of clinical success. Failure of this procedure can partially be explained by inadequate sealing of the root apices with resultant microleakage in the periapical area. OBJECTIVES: To assess and compare in vitro sealing ability of 3 different dental restorative materials used as apical sealants during equine surgical endodontics. METHODS: Thirty extracted equine cheek teeth were divided randomly into 3 groups and subjected to apicoectomy and apical sealing using 3 materials: reinforced zinc oxide-eugenol cement; intermediate restorative material (IRM); a resin-modified glass ionomer; and amalgam. After apical sealing, the teeth were submerged in a solution of Procion Brilliant Cresyl Blue stain for a period of 7 days. The teeth were then washed, embedded in resin, sectioned and assessed microscopically for dye leakage around the apical restorations. RESULTS: Although the materials proved effective as apical sealants, some dye leakage was encountered in all 3 groups with no statistical difference (P = 0.114). CONCLUSIONS AND POTENTIAL RELEVANCE: IRM, a resin-modified glass ionomer and amalgam all showed comparative features as apical sealants when used in vitro in equine teeth. IRM is currently regarded as the superior material in clinical situations due to its ease of handling and lesser sensitivity to environmental moisture during placement compared to the other 2 materials.

Diagnosis and treatment of primary intraoral leiomyosarcomas in four dogs.

This paper describes the clinical and pathological features, diagnosis and management of primary intraoral leiomyosarcomas in the oral cavity of four dogs; they involved the gingivae of the rostral maxilla and mandible, the mucosa of the upper lip and the soft palate. Their features are compared with the those of leiomyosarcomas commonly encountered in the gastrointestinal tract of dogs. Two of the dogs responded well to surgical treatment; one died after its airways were obstructed by a large palatal tumour; and the fourth was lost to follow-up after its owners declined treatment.

The suitability of paraffin-embedded material to predict metastatic potential of oral squamous cell carcinoma.

BACKGROUND: The presence of regional metastasis in oral squamous cell carcinoma (OSCC) is an important prognostic factor. This study was undertaken to identify histological features and biological markers from paraffin-embedded primary OSCC that may predict the presence of regional metastases. MATERIALS AND METHODS: Fifty-three en-bloc primary OSCC resections were divided into two groups, 26 with lymph node metastases and 27 without metastases. The pattern of infiltration, presence of vascular or perineural infiltration and tumour necrosis were evaluated while expression of p53, p21 and Rb were assessed in the two groups. DNA ploidy status was also determined with a flow cytometer. RESULTS: The presence of DNA aneuploidy was found to be the only statistically significant predictor of regional metastases. Seventy-seven per cent of the primary OSCC with lymph node metastases showed DNA aneurploidy. CONCLUSION: DNA flow cytometry obtained from archival material could be used as a parameter to predict regional metastases.