Alarming atrioventricular block and mitral valve prolapse in the Kearns-Sayre syndrome

Kearns-Sayre syndrome (KSS) is a multisystem mitochondrial disorder characterized by the invariant triad: onset before 20, progressive external ophthalmoplegia and pigmentary retinal degeneration, plus at least one of the following: complete (or not) heart block, cereberal dysfunction and CSF protein above 100 mg/dl. Autopsies from patients with KSS revealed widespread tissue distribution mtDNA deletions. These deletions result in significantly lower activities of the enzymes of the respiratory chain. The same deletion of mitochondrial DNA present in skeletal muscle is found in myocardial tissue. An 18-year-old girl diagnosed with the KSS was admitted to our hospital because of an upper respiratory tract infection and dysphagia. ECG showed cardiac conduction defects. The patient had no history of syncope. At her surface ECG there was a complete RBBB (QRS duration approximately 130 ms), a clockwise rotation with an axis of approximately 90 degrees and a slight QT prolongation (420 ms). Echocardiography showed prolapse with thickening and degeneration of both mitral valve leaflets but without mitral regurgitation. The patient was started on a diet rich in potassium and pharmaceutical therapy with magnesium oxide (240 mg of elemental Mg p.o. per day), 1 g of calcium carbonate t.i.d., vitamin D (calcitriol 0.25 microg p.o. per day) and coenzyme Q(10) 100 mg daily and discharged 6 days later with slightly improved biochemical profile but apparent clinical improvement. Urgent pacemaker implantation was decided but unfortunately the patient died due to acute cardiac arrest 10 days later.     

Dacryoscintigraphy for the detection of ocular drainage system stenosis induced by docetaxel and fluorouracil

Docetaxel (D) is an antineoplastic agent of the taxane group produced by fir needles and is used in the treatment of breast, lung, prostate, stomach as well as of head and neck cancers. It is usually administered in weekly or 3-weekly regimens. Some side-effects of D are neutropenic fever, anemia, fluid retention, hypersensitivity reactions, anorexia, myalgias, mucositis, mild alopecia, skin and nail toxicity, peripheral neuropathy, canalicular stenosis and/or obstruction, epiphora and tearing. Extensive fibrotic changes in the stroma of the lacrimal sac and the nasal mucosa are the prominent histologic features of the canalicular narrowing and nasolacrimal duct obstruction. Furthermore, studies in patients receiving D treatment showed that after intravenous infusion, D was usually secreted in tears causing ocular irritation. The histologic evidence of keratinization with marked epidermalization of the surface epithelium, thickening, and parakeratosis of the squamous epithelium, confirms fibrosis. Epiphora is a greek word meaning that the line of tears (phora) runs over the eye (epi). Epiphora is a clinical sign or condition, in which tears drain down the face rather than through the nasolacrimal system. Epiphora may also be due to ocular irritation and inflammation or to obstruction of tear outflow tract, ie. ectropion, punctal, canalicular or nasolacrimal obstruction. For punctal stenosis punctoplasty is performed, for subtotal stenosis a permanent silicone tube is advocated and for total stenosis a permanent bypass is required. Dacryoscintigraphy is a well established diagnostic tool for the eye drainage apparatus, and its importance in diagnosing functional lacrimal duct obstruction and even classifying the types of obstruction to predict postoperative results of silicone tube insertion has been reported by others. Chemotherapeutic drugs like D tend to be especially toxic to normal tissues and usually interfere with cell growth or proliferation. Thus, excessive tear production and epiphora, occur as a side effect of D, as the afflicted fibrosis disrupts the continuation of the membranous channel. Although the severity and frequency of epiphora is less with the 3-weekly dosing schedule of D, an incidence of almost 40% has been reported even for this schedule, especially during the longer treatment regimes for metastatic breast cancer. We report on two patients with epiphora and canalicular stenosis developed while on a 3-weekly D treatment regime. Both our patients agreed to be monitored with dacryoscintigraphy. The patients were seated in front of the low energy high resolution (LEHR) collimator of the gamma camera, and after applying 0.1mL of (99m)Tc-pertechnetate of 3.7 MBq on the conjunctiva near the internal canthus of each eyeball we recorded bilateral eyeball images. A dynamic scintigraphy of the area was obtained (9 frames of 1min duration each, followed by one 5min frame, matrix 64x64, LEHR collimator and no zoom), as the (99m)Tc-pertechnetate flows along the tear strips, through the nasolacrimal drainage system, into the nasal fossa. By using LEHR collimator, the canaliculi, the lacrimal sac, the nasolacrimal duct and the Hasner's valve area are normally visualized. When the flow in the lacrimal apparatus is impaired, dacryoscintigraphy will demonstrate the blockage and may also identify the site of obstruction. A follow-up with a second dacryoscintigraphy, a month after the end of D treatment, was performed. The first patient, a 59 years old woman was treated for metastatic breast cancer with D. She received a 3-weekly treatment regime of 75mg/m2 (130 mg in total) intravenously, with dexamethasone coverage for a total of 6 cycles. She reported extensive tearing 2 weeks after the second cycle, which did not improve after discontinuation of the drug. She was advised to use artificial tears and visit the ophthalmology clinic. She had been reluctant to undergo any procedures but at least she agreed to be monitored with dacryoscintigraphy. Initial imaging of the drainage apparatus by dacryoscintigraphy, when symptoms appeared, showed complete bilateral blockage at the lower canaliculus. The second patient, a 54 years old male with metastatic gastric carcinoma received a combination of docetaxel 75 mg/m2 (120mg in total), carboplatin 450mg and 6 pills capecitabine (xeloda) of 500mg each, in a weekly treatment regime (3 weeks treatment and one week intermission), with dexamethasone coverage for a total of 6 cycles. This patient had also refused to visit an ophthalmology clinic but followed our instructions to use artificial tears. The first dacryoscintigraphy was performed as soon as epiphora appeared, a few days after the first cycle of D treatment and the second, a month after the end of 6 cycles of D treatment. Both dacryoscintigraphies, showed a bilateral total blockage of the drainage apparatus in the area of the lower canaliculus. Despite his complaints and discomfort, this patient was also reluctant to undergo any other procedures. Capecitabine is a prodrug converted into fluorouracil (5FU) in the tissues. This combination may increase the possibility of dacryostenosis. The cytotoxic metabolites of 5FU interfere with DNA replication and RNA synthesis in rapidly proliferating tear duct cells and may occasionally cause canalicular stenosis with intractable epiphora and even fibrosis, which is difficult to manage. Furthermore, 5FU is also known to cause mucosal inflammation, conjunctivitis and GI tract inflammations. It may also be hypersecreted from the lacrimal gland, thus tears gaining access over the ocular surface may cause ocular surface toxicity and reflex tearing. The development of cicatricial ectropion further exacerbates the situation. The possibility that the above stenoses could be partly due to viral infection in an immunocompromised patient cannot be excluded. The incidence and severity of lacrimation correlates with the concentration of 5FU in tears but is not directly related to its plasma levels. Epiphora can have a negative impact on the quality of life, because it induces inability to read, drive, put on make up and gives the false impression of emotional tearing. If left untreated, epiphora may have a negative impact on visual function, with significantly lower visual acuity scores. Artificial tears and/or eye drops containing corticosteroids are suggested for treatment. Patients receiving D and/or 5FU should be closely followed by an ophthalmologist for an early diagnosis and treatment of epiphora that may prevent closure of ocular canaliculi. Nuclear dacryoscintigraphy is simple, fast, cheap, and harmless technique for this diagnosis and may replace a more uncomfortable and not so specific technique like the Schirmer's test, in which a filter paper is placed in the lower lid of the eye and the amount of tears is measured. It would be valuable to add the importance of dacryoscintigraphy in the differential diagnosis of pseudoepiphora, which encompasses reflex tearing caused by inflammation or dry eyes, nasal disease, like allergic rhinitis, polyps, tumors or rhinoplasty. It has been suggested that dacryoscintigraphy is the best method for measuring the dynamics of tear drainage especially in the canaliculi, although some prefer the CT dacryocystography, which gives a much higher radiation dose to the patient. In conclusion, we have described one patient with epiphora after docetaxel treatment and another after both docetaxel and 5FU treatment and emphasize the diagnostic value of dacryoscintigraphy.     

Effect of time interval on tissue concentrations of cephalosporins after tourniquet inflation: Highest levels achieved by administration 20 minutes before inflation

We studied the effect of different time intervals between antibiotic administration and tourniquet inflation in 62 patients undergoing reconstructive surgery in the lower extremities. The in vivo concentrations in soft tissue and bone of 3 cephalosporins (ceftazidime, ceftriaxone and ceforanide) were determined. Our findings suggest that the highest tissue concentrations were achieved by administration 20 min before tourniquet inflation.     

Upper Gastrointestinal (GI) pH in Young,Healthy Men and Women

The pH in the upper gastrointestinal tract of young, healthy men and women was measured in the fasting state and after administration of a standard solid and liquid meal. Calibrated Heidelberg capsules were used to record the pH continuously over the study period of approximately 6 hr. In the fasted state, the median gastric pH was 1.7 and the median duodenal pH was 6.1. When the meal was administered the gastric pH climbed briefly to a median peak value of 6.7, then declined gradually back to the fasted state value over a period of less than 2 hr. In contrast to the pH behavior in the stomach, feeding a meal caused a reduction in the median duodenal pH to 5.4. In addition, there was considerable fluctuation in the postprandial duodenal pH on an intrasubject basis. The pH in the duodenum did not return to fasted state values within the 4-hr postprandial observation period. There was no tendency for the duodenal pH to be related to the gastric pH in either the fed or fasted phases of the study. Furthermore, pH in the upper GI tract of young, healthy subjects appears to be independent of gender. The differences in upper GI pH between the fasted and the fed state are discussed in terms of dosage form performance and absorption for orally administered drugs.     

Metabolism of hexachloro-1,3-butadiene in mice: in vivo and in vitro evidence for activation by glutathione conjugation

1. The metabolism of 14C-hexachloro-1,3-butadiene (HCBD) was studied in mice and in subcellular fractions from mouse liver and kidney. 2. In the presence of glutathione (GSH), liver microsomes and cytosol transformed HCBD to S-(pentachlorobutadienyl)glutathione (PCBG). PCBG formation in subcellular fractions from mouse kidney was very limited. Oxidative metabolism of HCBD by cytochrome P-450 could not be demonstrated. 3. Cysteine conjugate beta-lyase was present in mitochondria and cytosol from mouse liver and kidney. 4. After an oral dose of 30 mg/kg 14C-HCBD, mice eliminated 67.5-76.7% of dose in faeces; urinary elimination accounted for 6.6-7.6%. 5. Metabolites of HCBD identified are: S-(pentachlorobutadienyl)glutathione in faeces; S-(pentachlorobutadienyl)-L-cysteine, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine and 1,1,2,3-tetrachlorobutenoic acid in urine. 6. The results suggest that conjugation of HCBD with GSH in liver, followed by renal processing of the glutathione S-conjugates and beta-lyase-catalysed formation of reactive intermediates, accounts for the organ specific toxicity of HCBD in mice.     

Enzymatic conjugation of hexachloro-1,3-butadiene with glutathione. Formation of 1-(glutathion-S-yl)-1,2,3,4,4-pentachlorobuta-1,3-diene and 1,4-bis(glutathion-S-yl)-1,2,3,4-tetrachlorobuta-1,3-diene

The glutathione-dependent metabolism of the nephrotoxin and nephrocarcinogen hexachloro-1,3-butadiene (HCBD) was investigated in subcellular fractions from rat liver and kidney. HCBD was metabolized by hepatic glutathione S-transferases to (E)- and (Z)-1-(glutathion-S-yl)-pentachlorobuta-1,3-diene (GPCB) in a ratio of 20:1, which were identified by secondary ion MS and by GC-MS after acid hydrolysis. The formation of GPCB was dependent on time and on protein and glutathione concentrations. Microsomal glutathione S-transferases from rat liver catalyzed GPCB formation more efficiently than did cytosolic glutathione S-transferases; very low rates of GPCB formation were observed in kidney subcellular fractions. GPCB is also a substrate for glutathione S-transferases and is metabolized to a diglutathione conjugate, which was identified by secondary ion MS and 13C NMR spectrometry as 1,4-bis(glutathion-S-yl)-1,2,3,4-tetrachlorobuta-1,3-diene (BTCB). BTCB formation from GPCB was dependent on time and on protein, glutathione, and GPCB concentrations. Hepatic cytosol catalyzed BTCB formation more efficiently than did hepatic microsomes; significant amounts of BTCB were also formed in kidney cytosol. Hepatic formation of glutathione S-conjugates, translocation of the S-conjugates to the kidney, and renal processing to form reactive intermediates may be the cause of HCBD-induced nephrotoxicity and, perhaps, nephrocarcinogenicity.     

The role of physical and psychological symptoms in desire for death: a study of terminally ill cancer patients

The current study assessed the attitudes of the desire for hastened death in terminally ill cancer patients and whether these are determined by their physical and psychological symptoms. The final sample consisted of 106 terminally ill cancer patients attending a Palliative Care Unit, in University of Athens, Greece, between June and October 2004. Significant associations were found between the desire for hastened death (D.H.D.) and 'pain' (r=0.469, p<0.005), 'fatigue' (r=0.591, p<0.0005), 'loss of appetite' (r=0.622, p<0.0005) and 'feeling sad' (r=0.635, p<0.0005). Statistically significant associations were also found between Schedule of Attitudes towards Hastened Death (SAHD) scores, age (r=0.300, p=0.002) and ECOG (p<0.0005). Twenty-six percent of the patients reported high D.H.D. while 41% reported moderate desire. In the prediction of SHAD the contribution of 'pain' (p=0.011), 'lack of appetite' (p=0.012) and 'sadness' (p=0.011) is high (42% of variance). Further findings suggest that D.H.D. is significantly related to 'feeling sad', 'lack of appetite', 'pain' and 'fatigue' after controlling for age, gender and performance status according to ECOG in terminally ill cancer patients.     

Analysis of renal cell transformation following exposure to trichloroethene in vivo and its metabolite S-(dichlorovinyl)-L-cysteine in vitro

Trichloroethene (TCE) is classified as a potential human carcinogen although there is a significant debate regarding the mechanism of TCE induced renal tumor formation. This controversy stems in part from the extremely high doses of TCE required to induce renal tumors and the potential contribution of the associated nephrotoxicity to tumorigenesis. We have used Eker rats, which are uniquely susceptible to renal carcinogens, to determine if exposures to TCE in vivo or exposure to its metabolite S-(dichlorovinyl)-L-cysteine (DCVC) in vitro can transform kidney epithelial cells in the absence of cytotoxicity. Treatment with TCE (0, 100, 250, 500, 1000 mg/kg bw by gavage, 5 days a week) for 13 weeks resulted in a significant increase in cell proliferation in kidney tubule cells, but did not enhance formation of preneoplastic lesions or tumor incidence in Eker rat kidneys as compared to controls. In vitro, concentrations of DCVC, which reduced cell survival to 50%, were able to transform rat kidney epithelial cells. However, no carcinogen-specific mutations were identified in the VHL or Tsc-2 tumor suppressor genes in the transformants. Taken together, the inability of TCE to enhance formation of preneoplastic changes or neoplasia and the absence of carcinogen-specific alteration of genes accepted to be critical for renal tumor development suggest that TCE mediated carcinogenicity may occur secondary to continuous toxic injury and sustained regenerative cell proliferation.