ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome

Introduction

Adenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT).

Methods

Measurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening.

Results

Ten out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6–71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1–8.9). All but one patient with SCID had T-B-NK? phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T>C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients.

Conclusion

The genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.

     

Diagnostic ultrasound treatment increases the bone fracture-healing rate in an internally fixed rat femoral osteotomy model.

OBJECTIVE: To investigate the healing effects of diagnostic ultrasound in a standardized rat femur fracture model. METHODS: Thirty-two male rats aged 14 weeks were used, and each rat's right femur was osteotomized and stabilized under anesthesia. The rats were then divided into 4 groups. Five days after surgery, ultrasound was applied every fifth day with diagnostic sonographic equipment and a probe with a 7.5-MHz frequency and 11.8-mW/cm2 total output intensity for 10 minutes in each session. Ultrasound was applied 8 times in group A, 3 times in group B, and only once in group C. Ultrasound was not applied to sham-operated group D. Healing and callus formation of the rats' femur fractures were evaluated by radiography and dual-energy x-ray absorptiometry. RESULTS: Dual-energy x-ray absorptiometric and radiographic results showed that the ultrasound therapy accelerated the fracture healing. Radiographically, groups A and B showed better fracture healing than groups C and D. Ultrasound exposure increased both the whole-bone mineral density and the density at the fracture region, increasing in parallel with the exposure period. CONCLUSIONS: This study confirms the previously shown efficacy of low-intensity ultrasonic stimulation in acceleration of the normal fracture repair process even when performed with a diagnostic sonographic device.     

High frequency of aspirin resistance in patients with acute coronary syndrome

Aspirin is widely used for secondary prevention of cardiovascular disease, but is not effective for all patients. This phenomenon is called as aspirin resistance. Although the prognosis is worse in patients who develop acute coronary syndrome (ACS) while using aspirin, the frequency of aspirin resistance in these patients has not been evaluated. We aimed to evaluate the frequency of aspirin resistance in patients with ACS and to determine its relationship with the angiographic severity and extent of the associated coronary artery disease. The present study included 104 patients with ACS (75 men, 60.4 +/- 10.8 years) who were hospitalized while using aspirin for at least last 7 days and 100 patients with stable coronary artery disease (73 men, 57.6 +/- 10.6 years), documented by coronary angiography, history of revascularization or myocardial infarction (MI), and the use of aspirin for last 7 days. The latter group had no MI or ACS for last 3 months. Platelet function was assessed with PFA-100, which simulates primary homeostasis at injured blood vessels. Coronary angiography was performed in 83 cases of the patients with ACS during hospital stay. Aspirin resistance is more prevalent in patients with ACS (40.3%) when compared with stable coronary artery disease patients (27%). The difference was statistically significant (p = 0.04). The ACS patients with aspirin resistance were older and had severe myocardial damage. However, there were no significant differences in angiographic severity and extent of coronary artery disease between aspirin-resistant and aspirin-sensitive patients. Frequency of aspirin resistance is higher in patients who develop ACS while using aspirin than that in patients with stable coronary artery disease.     

Investigation of neuromuscular transmission in some rare types of migraine

The aim of this study was to delineate any dysfunction of neuromuscular transmission (NMT) by single-fibre electromyography (SFEMG) in some rare types of migraine. Recent studies have shown subclinical dysfunction of NMT in migraine with aura and cluster headache by using SFEMG, whereas another recent study has shown NMT to be normal in familial hemiplegic migraine (FHM) with CACNA1A mutations. Thirty patients with rare primary headache syndromes [18 with sporadic hemiplegic migraine (SHM), six with FHM and six with basilar-type migraine (BM)] and 15 healthy control subjects without any headache complaints underwent nerve conduction studies, EMG and SFEMG during voluntary contraction of the extensor digitorum communis muscle. Ten to 20 different potential pairs were recorded and individual jitter values calculated. The results obtained from patient groups were compared with those from the normal subjects. Of 600 individual jitter values of the patients, 27 (4.5%) were abnormally high, whereas only 3/205 (1.5%) jitter values from normal subjects were abnormal. Abnormal NMT was found in 4/30 (13.3%) patients (three SHM and one BM), but in none of the control subjects. Only in SHM patients was the number of individual abnormal jitter values slightly but significantly different from normal controls. The present study demonstrates that subclinical NMT abnormality is slightly present in only SHM and BM patients, but not in FHM patients.     

Intraductal growth-type mucin-producing peripheral cholangiocarcinoma associated with biliary papillomatosis

A 64-year-old woman with upper abdominal pain, nausea, and vomiting was admitted. The magnetic resonance imaging revealed marked dilation and "crowding" of the segment 4 bile ducts with an area suspicious for a stone or tumor. Ultrasonography-guided percutaneous transhepatic cholangiography revealed multiple filling defects in the segment 4 bile ducts, the left and common hepatic ducts. A left hepatectomy and cholecystectomy was performed. Dilated bile ducts containing mucinous material and a mass in the cystically dilated bile ducts of segment 4 were detected in the gross examination. It showed continuity within the surrounding dilated bile ducts. The dilated bile ducts of the segments 2 and 3 contained mucinous material without any apparent mass formation. Microscopically, the bile ducts were lined by biliary epithelium displaying simple and complex papillary structures with moderate to severe degree of dysplastic changes. The mass was composed of complex papillary structures filling the bile duct with a few foci of invasion. The papillary structures were composed of mucin-producing columnar cells as well as cells with oncocytic appearance. Patchy cytokeratin 7, cytokeratin 19, hepatocyte paraffin 1, MUC2, and CDX2 immunopositivities were observed. Biliary papillomatosis, mucin-producing intrahepatic cholangiocarcinoma, and intraductal papillary-type peripheral cholangiocarcinoma are in the same disease spectrum of papillary biliary neoplasm and termed as intraductal papillary neoplasm of the liver. Mucinous hypersecretion and signs of mucobilia are considered specific and should raise the suspicion of lesions in this spectrum.     

Biofilm formation by Staphylococcus epidermidis on nitrogen ion implanted CoCrMo alloy material

Staphylococcus epidermidis is the primary cause of medical device-related infections due to its adhesion and biofilm forming abilities on biomaterial surfaces. For this reason development of new materials and surfaces to prevent bacterial adhesion is inevitable. In this study, the adhesion of biofilm forming S. epidermidis strain YT-169a on nitrogen (N) ion implanted as well as on as-polished CoCrMo alloy materials were investigated. A medical grade CoCrMo alloy was ion implanted with 60 keV N ions to a high dose of 1.9 x 10(18) ions/cm(2) at substrate temperatures of 200 and 400 degrees C. The near-surface implanted layer crystal structures, implanted layer thicknesses, and roughnesses were characterized by XRD, SEM and AFM. The number of adherent bacteria on the surfaces of N implanted specimens was found to be 191 x 10(6) CFU/cm(2) for the 200 degrees C and 70 x 10(6) CFU/cm(2) for the 400 degrees C specimens compared to the as-polished specimen (3 x 10(6) CFU/cm(2)). The adhesion test results showed that S. epidermidis strain YT-169a adhere much more efficiently to the N implanted surfaces than to the as-polished CoCrMo alloy surface. This was attributed mainly to the rougher surfaces associated with the N implanted specimens in comparison with the relatively smooth surface of the as-polished specimen.     

Treatment with lithium, alone or in combination with olanzapine, relieves oxidative stress but increases atherogenic lipids in bipolar disorder

The changes in antioxidant-oxidant balance play important roles in the pathophysiology of neuropsychiatric conditions. Bipolar disorder (BD) is a psychiatric condition with recurrent mood disturbances. This study evaluates the effects of treatment with lithium, alone or in combination with antipsychotic olanzapine, on oxidant-antioxidant status and atherogenic character in patients with BD. The blood samples from 15 patients were tested before the treatment (pre-treatment phase) and at the ends of two consecutive treatment periods: period I, treatment with lithium and an antipsychotic drug, olanzapine (first 6 months) and period II, treatment with only lithium (6 months following period I). We measured serum atherogenic lipids (total cholesterol, triglycerides, and LDL-cholesterol), plasma lipid peroxides (thiobarbituric acid-reactive substances), antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) in neutrophils and lymphocytes, and total antioxidant status in plasma. Compared with pre-treatment phase, the lipid parameters were increased with each treatment; especially, LDL-cholesterol was significantly increased only with lithium treatment. These findings alert to be cautious about use of lithium in patients with atherogenic conditions. Moreover, plasma lipid peroxides were decreased significantly after the combination therapy and further decreased with lithium treatment. Antioxidant enzyme activities in lymphocytes were decreased after both types of treatment. Importantly, plasma total antioxidant status was increased only with lithium treatment. Thus, treatment with lithium alone decreases already up-set oxidant status in BD. In conclusion, the combination therapy with olanzapine is better in terms of atherogenic profile, while lithium alone produces better antioxidant status in patients with BD.     

Nonsurgical endodontic treatments in molar teeth with large periapical lesions in children: 2-year follow-up

Profound caries lesions may lead to invasion of microorganisms to the dental pulp, and periapical areas can promote the development of dentoalveolar abscess and periapical bone loss. Treatment options to manage large periapical lesions range from nonsurgical root canal treatment and/or apical surgical procedure to extraction. Young molar teeth with pulp necrosis and large periapical lesions in children are frequently treated with root canal treatment because the therapy is more difficult in multirooted teeth. In these case reports, nonsurgical endodontic treatments performed on 6 molar teeth with large periapical lesions, by repeated intracanal dressing with calcium hydroxide, are presented. Radiographs displayed significant bony healing at the end of the second year. In conclusion, large periapical lesions can respond favorably to nonsurgical treatment, and complex and difficult endodontic treatments in children might not be required.     

Localization of the marginal mandibular branch of the facial nerve

The aim of this study was to observe the course of the marginal mandibular branch of the facial nerve (MMBFN) in relation to the inferior border of the mandible and parotid gland and its relevance to surgical procedures such as rhytidectomy and parotid gland surgery. In this study, 50 specimens were dissected. The relationships between the MMBFN and the inferior border of the mandible were recorded and analyzed. We found that posterior to the facial artery, the MMBFN ran above the inferior border of the mandible in 37 (74%) of the specimens. In 11 (22%) specimens, below the inferior border of the mandible it was divided into two branches at the crossing point with the facial artery. In 2 (4%) specimens the MMBFN divided into two branches at the point of emergence from the parotid gland. There were no statistical differences between the left and right sides, and both sexes. The MMBFN is one of the most vulnerable branches to surgical injury because of its location. For this reason, the surgeons who are willing to operate on this area, especially for the rhytidectomies, should have a true knowledge about the anatomy of this branch.     

Color change evaluation of denture soft lining materials in coffee and tea

This study evaluated the color stability of soft denture liners after being exposed to coffee and tea solutions for different time periods. Four soft denture liners and a denture base polymer were tested. Five specimens of each material were immersed in either coffee or tea solution at 50 +/- 1 degrees C for one, three, nine, 24, 48, and 96 hours. Color measurements were made using a reflectance spectrophotometer before and after the specimens were exposed to the solutions. After 96 hours' immersion in coffee and tea solutions, coffee produced more marked color changes than did tea for all the materials tested. Surface roughness (Ra) of the materials after being cured against a stainless steel surface was also measured with a contact-type surface roughness measuring instrument. Due to the different surface structures, which thus accounted for the different Ra values, the materials behaved differently when immersed in different solutions.