MERRF and Kearns-Sayre overlap syndrome due to the mitochondrial DNA m.3291T>C mutation.

A 48-year-old man presented with a complex phenotype of myoclonus epilepsy with ragged-red fibers (MERRF) syndrome and Kearns-Sayre syndrome (KSS), which included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy, bifascicular heart block, and ragged-red fibers. The m.3291T>C mutation in the tRNA(Leu(UUR)) gene was found with 92% heteroplasmy in muscle. This mutation has been reported with MELAS, myopathy, and deafness with cognitive impairment. This is the first description with a MERRF/KSS syndrome.

Myopathy and parkinsonism in phosphoglycerate kinase deficiency.

A 25-year-old man with exertional myoglobinuria had no evidence of hemolytic anemia, but he had severe parkinsonism that was responsive to levodopa. Phosphoglycerate kinase (PGK) activity was markedly decreased in muscle, and molecular analysis of the PGK1 gene identified the p.T378P mutation that was recently reported in a patient with isolated myopathy. This case reinforces the concept that PGK deficiency is a clinically heterogeneous disorder and raises the question of a relationship between PGK deficiency and idiopathic juvenile Parkinson disease.

Combined nutritional support in patients with chronic obstructive pulmonary disease (COPD), under mechanical ventilation (MV).

BACKGROUND/AIMS: The importance of nutrition is clearly established in the management of the critically ill patient: malnutrition contributes to immune incompetence, poor wound healing, increased postoperative complication and prolonged hospital stay. The interaction between nutritional status, nutritional supply and respiratory function is important in the management of the Chronic Obstructive pulmonary Disease (COPD) patients under mechanical ventilation (MV). In the present study was analyzed the benefits of combined nutritional support in patients with COPD under MV. METHODOLOGY: One hundred ninety two (192) patients with COPD were admitted to our Intensive Care Unit (ICU), due to severe respiratory failure of whom 163 (84.9%) patients were under MV. In 18 (11.04%) patients after the 10th day under MV and due to severe malnutrition (serum albumin < 2.5 gm/dl, total lymphocyte count (TLC) < 900/mm3), added in the enteral nutrition (EN) of 1800 Kcals and parenteral nutrition (PN) of 2000 Kcals, at high concentration in lipids from central venous catheter. RESULTS: Seven (38.89%) patients on the 4th day, after combined nutrition, had a positive balance of nitrogen and normal level of the nutritional indices, 4 (22.22%) were on normal level on the 5th day, 3 (16.67%) on the 6th day, 1 (5.56%) on the 7th day after combined nutrition. We had no complications from the combination of EN and PN. Conclusively, of these 18 patients that were given both EN and PN, 15 (83.33%) were weaned from MV and continued the combined nutritional support for 3 days, while 3 (16.67%) died during the combination of EN and PN, without having achieved a normal level of the indices of nutrition and without a positive balance of nitrogen. CONCLUSIONS: In this study was found that: 1. patients with COPD under MV rapidly developed malnutrition, 2. the combination EN and PN without complications contribute to the weaning from MV, 3. positive nitrogen balance and normal increases of nutrition are achieved after the 4th day of combined nutrition and 4. Early addition of EN and PN in patients with COPD under MV, probably accelerates the weaning from MV, reduces hospitalization, changes the outcome and reduces the cost of hospitalization of patients with COPD under MV in ICU.

Preoperative pulmonary evaluation (PPE) as a prognostic factor in patients undergoing upper abdominal surgery.

BACKGROUND/AIMS: Upper abdominal operations are relatively high risk for postoperative pulmonary complications. The influences of general anesthesia and an operative procedure are well known to negatively impact pulmonary gas exchange. For this reason, the preoperative pulmonary evaluation (PPE) should emphasize risk factors for pulmonary complications. The prediction of these complications is still an under-investigated field. The aim of this study is to identify risk indicators for pulmonary complications after elective upper abdominal operations. METHODOLOGY: A standardized PPE was performed on 28 patients (mean age 53 years) who were admitted to the Intensive Care Unit (ICU) of the Hospital of Athens after scheduled extensive upper abdominal surgery. The PPE included physical examination, medical history, smoking history and general laboratory tests including chest X-ray, and arterial blood gases and spirometry. The type of surgical operation and duration of anesthesia were also evaluated. Postoperatively, data was collected on the occurrence of a symptomatic and clinically significant pulmonary complication. RESULTS: All 28 patients (57.2% female, 42.8% male) needed mechanical ventilator (MV) support after surgery because of respiratory failure and the mean time of MV was 4 +/- 2 days. During this period, 6 (21.4%) patients developed nosocomial pneumonia, 3 (10.7%) developed acute respiratory distress syndrome (ARDS), 2 (6.1%) had a small atelectasis and 4 (14.2%) developed bleeding disorders. Eventually, 2 (7.1%) of the patients with ARDS developed sepsis and died during hospitalization in ICU. All patients who developed complications had a medical history of mild COPD, chronic obstructive pulmonary disease (COPD), a smoking history, were operated on for underlying malignancies and also had abnormal preoperative laboratory results. CONCLUSIONS: Pulmonary complications have enormous implications for the patient and the health care system. The first step in reducing postoperative complications is to identify which patients are at increased risk. PPE is the better way to select clinical and laboratory factors that allow risk stratification for postoperative pulmonary complications after upper abdominal surgery.

Approach to patients with pulmonary embolism in a surgical intensive care unit.

BACKGROUND/AIMS: Pulmonary embolism (PE) is a potentially life threatening disease. Clinical signs and symptoms allow the clinician to determine the pretest probability of someone having pulmonary embolism but are insufficient to diagnose or rule out the condition. This paper aims to study the clinical presentation, identify the risk factors and evaluate the diagnostic strategies and management of patients with PE. METHODOLOGY: The medical files of 69 patients were searched, who were diagnosed with PE and who were admitted to the Surgical Care Unit. RESULTS: Dyspnea, pleuritic pain, haemoptysis, fever and cough were the most common presenting symptoms. Risk factors for PE were found in 90% of cases. D-dimers assay was elevated in all cases (100%) and the other diagnostic strategies used showed great accuracy in confirming the pretest probabilities of PE. It is of high importance that 75% of the patients had deep vein thrombosis as assessed by venous ultrasonography. Mortality due to PE was approximately 6.9%. CONCLUSIONS: PE can be often overlooked with hazardous consequences. Clinical evaluation in combination with spiral CT or lung scintigraphy and vein ultrasound and D-dimer level can establish the diagnosis in the majority of patients so that effective treatment to be started as soon as possible.

A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome.

Mutations in the mitochondrial DNA cytochrome b gene (MTCYB) have been commonly associated with isolated mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders, and only once with a parkinsonism/mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) overlap syndrome. Here, we describe a novel mutation (m.14864 T>C) in MTCYB in a 15-year-old girl with a clinical history of migraines, epilepsy, sensorimotor neuropathy, and strokelike episodes, a clinical picture reminiscent of MELAS.  The mutation, which changes a highly conserved cysteine to arginine at amino acid position 40 of cytochrome b, was heteroplasmic in muscle, blood, fibroblasts, and urinary sediment from the patient but absent in accessible tissues from her asymptomatic mother. This case demonstrates that MTCYB must be included in the already long list of mitochondrial DNA genes that have been associated with the MELAS phenotype.

Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNA(Ile) mutation.

The differential diagnosis of myoglobinuria includes multiple etiologies, such as infection, inflammation, trauma, endocrinopathies, drugs toxicity, and primary metabolic disorders. Metabolic myopathies can be due to inherited disorders of glycogen metabolism or to defects of fatty acid oxidation. Primary respiratory chain dysfunction is a rare cause of myoglobinuria, but it has been described in sporadic cases with mutations in genes encoding cytochrome b or cytochrome c oxidase (COX) subunits and in four cases with tRNA mutations. We describe a 39-year-old woman with myalgia and exercise-related recurrent myoglobinuria, who harbored a novel mitochondrial DNA mutation at nucleotide 4281 (m.4281A>G) in the tRNA-isoleucine gene. Her muscle biopsy revealed ragged-red and COX-deficient fibers. No deletions or duplication were detected by Southern blot analysis. The m.4281A>G mutation was present in the patient's muscle with a mutation load of 46% and was detected in trace amounts in urine and cheek mucosa. Single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient (65%) than in normal fibers (45%). This novel mutation has to be added to the molecular causes of recurrent myoglobinuria.

The m.3244G>A mutation in mtDNA is another cause of progressive external ophthalmoplegia.

We sequenced all mitochondrial tRNA genes in a 61-year-old man with chronic progressive external ophthalmoplegia and mitochondrial myopathy but without mtDNA rearrangements, and identified a heteroplasmic m.3244G>A mutation in the tRNA(Leu(UUR)) gene. This mutation had been previously associated with the MELAS phenotype, but not described in any detail. The mutation load in muscle was 84% and COX-negative fibers harbored greater levels of mutant genomes than COX-positive fibers. The m.3244G>A mutation affects a highly conserved nucleotide in the dihydrouridine loop and has been associated with a wobble modification deficiency of the mutant tRNA.

Bone microenvironment-related growth factors modulate differentially the anticancer actions of zoledronic acid and doxorubicin on PC-3 prostate cancer cells.

OBJECTIVES: We analyzed the actions of zoledronic acid (10-250 microM) and doxorubicin (10-250 nM) on PC-3 prostate cancer cells using both continuous (48-96 hr) and pulsatile exposures (15 min/day for up to three consecutive days). RESULTS: The proliferation of PC-3 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner. In contrast, pulsatile exposures of doxorubicin failed to inhibit the growth of PC-3 cells. In addition, the inhibition of PC-3 cells by zoledronic acid was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), however, not by farnesyl pyrophosphate (FPP). Furthermore, exogenous administration of transforming growth factor beta 1 (TGF-beta1), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and more potently, insulin-like growth factor 1 (IGF-1) inhibited the doxorubicin-induced apoptosis of PC-3 cells. Under identical experimental conditions, these growth factors failed to alter the cytotoxicity of PC-3 cells induced by zoledronic acid. CONCLUSIONS: These data suggest that (i) repetitive and pulsatile (15 min/day) exposure to zoledronic acid inhibited the growth of PC-3 cells, (ii) this anticancer action of zoledronic acid was partially mediated by the attenuation of GGPP production, and (iii) bone microenvironment-related growth factors do not alter the anticancer actions of zoledronic acid on PC-3 cells.