Appendix carcinoid associated with the Peutz-Jeghers syndrome.

INTRODUCTION: The Peutz-Jeghers syndrome (PJS) is a rare hereditary, autosomal-dominant disorder. It is characterized by a gastrointestinal polyposis and mucocutaneous melanic spots. It has also been reported as a precondition for malignancies with a life-time-hazard for cancer up to 93%, caused by a germline mutation in the STK11 gene. PRESENTATION OF CASE: A 21-year-old man presented with nausea and abdominal pain. He had a known history of PJS since the age of 13 when he was treated for intussusception due to a hamartomatous polyp. Preoperative diagnostics revealed a second intussusception and an extensive intestinal polyposis. Intraoperative findings confirmed the suspected diagnoses and desvagination was performed. Nearly 50 polyps were removed from the small intestinum over several longitudinal sections. As the appendix appeared thickened an appendectomy was performed simultaneously. Histology showed hamartomatous polyps and the incidental finding of a pT1 carcinoid of the appendix. The patient recovered well and needed no further treatment for his carcinoid tumor. DISCUSSION: The mechanism of carcinogenesis in PJS still remains debatable, although the genetic disorder underlying the syndrome is known. A predisposition for carcinoid tumors also stays questionable. To our knowledge there is no description of an association between carcinoid tumors of the appendix and PJS to date. CONCLUSION: Life-expectancy in patients with PJS is reduced. Causes are the development of malignancies and complications from the polyps such as intussusception. Since there is no treatment possible main focus must be aimed at early recognition of malignancies and the prevention of complications.

Visual AIDS for multimodal treatment options to support decision making of patients with colorectal cancer.

BACKGROUND: A variety of multimodal treatment options are available for colorectal cancer and many patients want to be involved in decisions about their therapies. However, their desire for autonomy is limited by lack of disease-specific knowledge. Visual aids may be helpful tools to present complex data in an easy-to-understand, graphic form to lay persons. The aim of the present study was to evaluate the treatment preferences of healthy persons and patients using visual aids depicting multimodal treatment options for colorectal cancer. METHODS: We designed visual aids for treatment scenarios based on four key studies concerning multimodal treatment of colorectal cancer. The visual aids were composed of diagrams depicting outcome parameters and side effects of two treatment options. They were presented to healthy persons (n = 265) and to patients with colorectal cancer (n = 102). RESULTS: Most patients and healthy persons could make immediate decisions after seeing the diagrams (range: 88%-100%). Patients (79%) chose the intensive-treatment option in the scenario with a clear survival benefit. In scenarios without survival benefit, all groups clearly preferred the milder treatment option (range: 78% - 90%). No preference was seen in the scenario depicting equally intense treatment options with different timing (neoadjuvant vs. adjuvant) but without survival benefit. CONCLUSIONS: Healthy persons' and patients' decisions using visual aids seem to be influenced by quality-of-life aspects rather than recurrence rates especially in situations without survival benefit. In the future visual aids may help to improve the management of patients with colorectal cancer.

Traumatic diaphragmatic ruptures: clinical presentation, diagnosis and surgical approach in adults.

OBJECTIVE: Traumatic diaphragmatic injuries are rare, but potentially life-threatening due to herniation of abdominal organs into the pleural cavities. They can be easily overlooked on initial diagnostics and a high index of suspicion is required. The aim of this retrospective study was to analyze the clinical presentation, diagnostic methods and surgical management of patients with diaphragmatic rupture at our institution. METHODS: A retrospective study was performed to analyze our experience with patients suffering from traumatic diaphragmatic rupture. Charts were reviewed for sex, age, side-location, concomitant injuries, time-to-diagnosis, diagnostic methods, surgical approach and outcome. RESULTS: Fourteen patients (median age: 46 yrs, range 18-71, 9 male, 5 female) with diaphragmatic injuries (left side: 10, right side: 4) were treated between July 2003 and September 2011. Mechanism of injury was a penetrating trauma (14%), blunt trauma (50%) and others (36%). Associated abdominal injuries included spleen rupture (n=3), liver laceration (n=2), abdominal wall laceration (n=2) and gastric perforation (n=1). Computed tomography was the most sensitive diagnostic method. All patients underwent trans-abdominal repair of the diaphragmatic defect (direct suture: 10, prosthetic mesh insertion: 4). Associated abdominal procedures included splenectomy (n=3), liver packing (n=2), abdominal wall reconstruction (n=2) and partial gastric resection (n=1). Morbidity and hospital mortality rate were 36% and 0%, respectively. Median postoperative hospital stay was 17 days (range: 7-40 days). CONCLUSION: Morbidity and mortality of diaphragmatic ruptures are mainly determined by associated injuries or complications of diaphragmatic herniation like incarceration of viscera or lung failure. Early diagnosis helps to prevent severe complications. Spiral CT-scan is the most reliable tool for acute diagnosis of diaphragmatic rupture and associated visceral lacerations. Laparotomy is an adequate surgical approach for diaphragmatic repair, especially in cases of associated abdominal organ injury.

Leigh-like subacute necrotising encephalopathy in Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and mitochondrial DNA.

Our knowledge of molecular mechanisms underlying mitochondrial disorders in humans has increased considerably during the past two decades. Mitochondrial encephalomyopathies have sporadically been reported in dogs. However, molecular and biochemical data that would lend credence to the suspected mitochondrial origin are largely missing. This study was aimed to characterise a Leigh-like subacute necrotising encephalopathy (SNE) in Yorkshire Terriers and to shed light on its enzymatic and genetic background. The possible resemblance to SNE in Alaskan Huskies and to human Leigh syndrome (LS) was another focus of interest. Eleven terriers with imaging and/or gross evidence of V-shaped, non-contiguous, cyst-like cavitations in the striatum, thalamus and brain stem were included. Neuropathological examinations focussed on muscle, brain pathology and mitochondrial ultrastructure. Further investigations encompassed respiratory-chain activities and the mitochondrial DNA. In contrast to mild non-specific muscle findings, brain pathology featured the stereotypic triad of necrotising grey matter lesions with relative preservation of neurons in the aforementioned regions, multiple cerebral infarcts, and severe patchy Purkinje-cell degeneration in the cerebellar vermis. Two dogs revealed a reduced activity of respiratory-chain-complexes I and IV. Genetic analyses obtained a neutral tRNA-Leu(UUR) A-G-transition only. Neuropathologically, SNE in Yorkshire Terriers is nearly identical to the Alaskan Husky form and very similar to human LS. This study, for the first time, demonstrated that canine SNE can be associated with a combined respiratory chain defect. Mitochondrial tRNA mutations and large genetic rearrangements were excluded as underlying aetiology. Further studies, amongst relevant candidates, should focus on nuclear encoded transcription and translation factors.

Subcomplexes of human ATP synthase mark mitochondrial biosynthesis disorders.

METHODS: We describe biochemically and clinically relevant aspects of mitochondrial ATP synthase, the enzyme that supplies most ATP for the cells energy demand. RESULTS: Analyzing human Rho zero cells we could identify three subcomplexes of ATP synthase: F1 catalytic domain, F1 domain with bound natural IF1 inhibitor protein, and F1-c subcomplex, an assembly of F1 domain and a ring of F(O)-subunits c. Large amounts of F1 subcomplexes accumulated also in mitochondria of patients with specific mitochondrial disorders. By quantifying the F1 subcomplexes and other oxidative phosphorylation complexes in parallel, we were able to discriminate three classes of defects in mitochondrial biosynthesis, namely, mitochondrial DNA depletion, mitochondrial transfer RNA (tRNA) mutations, and mutations in the mitochondrial ATP6 gene. INTERPRETATION: The relatively simple electrophoretic assay used here is a straightforward approach to differentiate between various types of genetic alterations affecting the biosynthesis of oxidative phosphorylation complexes and will be useful to guide molecular genetic diagnostics in the field of mitochondrial neuromuscular disorders.

Functional and mutational characterization of human MIA40 acting during import into the mitochondrial intermembrane space.

A first component involved in import into the mitochondrial intermembrane space, named Mia40, has been described recently in yeast. Here, we identified the human MIA40 as a novel and ubiquitously expressed component of human mitochondria. It belongs to a novel protein family whose members share six highly conserved cysteine residues constituting a -CXC-CX9C-CX9C- motif. Human MIA40 is significantly smaller than the fungal protein and lacks the N-terminal extension including a transmembrane region and mitochondrial targeting signal. It forms soluble complexes within the intermembrane space of human mitochondria. Depletion of MIA40 in human cells by RNA interference specifically affected steady-state levels of small and cysteine-containing intermembrane space proteins like DDP1 and TIM10A, suggesting that MIA40 acts along the import pathway into the intermembrane space. Studies on the in vivo redox state of human MIA40 demonstrated that it contains intramolecular disulfide bonds. Thiol-trapping assays revealed the co-existence of different oxidation states of human MIA40 within the cell. Furthermore, we show that the twin -CX9C- motif is specifically required for import and stability of MIA40 in mitochondria. Partial mutation of this motif affects stable accumulation of MIA40 in the intermembrane space, whereas mutation of all cysteine residues in this motif inhibits import in mitochondria. Taken together, we conclude that the biogenesis and function of MIA40 in the mitochondrial intermembrane space is dependent on redox processes involving conserved cysteine residues.

Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene.

The Mohr-Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early-onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness-dystonia peptide (DDP1/TIMM8a) gene on the X-chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone-like manner to facilitate the import of nuclear-encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy-generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico-cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.