Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Mohebbi N, Vargas‐Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wüthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near‐normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non‐consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.     

Erosive mucosal lichen planus and secondary epiphora responding to systemic cyclosporin A treatment

Erosive mucosal lichen planus (LP) is a well-established variant of LP characterized by the formation of ulcerative lesions predominantly involving the oral and genital mucosae. Less commonly, this condition may involve oesophageal and/or ocular mucosal surfaces, and case reports within the ophthalmology literature have recently confirmed the potential for this condition to affect the nasolacrimal ducts. We report the case of a woman with severe cicatrizing mucosal LP and ocular symptoms secondary to presumed nasolacrimal duct involvement. We also report the potential for this newly appreciated manifestation of LP to respond to systemic cyclosporin A.     

Ductus venosus blood flow assessment at 11 to 14 weeks of gestation and fetal outcome.

OBJECTIVE: To evaluate the association between abnormal ductus venosus (DV) at 11-14 weeks' gestation and chromosomal abnormalities, structural defects and fetal outcome. METHODS: DV flow-velocity waveform (DV-FVW) and nuchal translucency thickness (NT) were prospectively evaluated in 1217 singleton pregnancies. RESULTS: The DV-FVW was abnormal in 84 fetuses, NT was above the 95th centile in 160 fetuses and both markers were observed in 41 fetuses. Chromosomal defects were diagnosed in 22 fetuses. The sensitivity, specificity and positive and negative predictive values for an abnormal karyotype were 86.4%, 86.9%, 11.9% and 99.7%, respectively, for an increased NT. These values were 68.2%, 96.9%, 31.3% and 99.3%, respectively, for DV-FVW abnormalities and 68.2%, 97.6%, 36.6% and 99.3%, respectively, when both markers were found simultaneously. Regarding structural defects, these values were 43.8%, 92.9%, 8.3% and 99.1% for an abnormal NT, 25.0%, 92.6%, 4.8% and 98.8% for DV-FVW abnormalities and 25.0%, 97.9%, 15.4% and 98.9% for both together. Considering those cases of unexplained fetal demise, the values were 44.4%, 85.9%, 5.0% and 98.9% for NT abnormalities, 22.2%, 92.6%, 4.8% and 98.6% for an abnormal DV-FVW and 22.2%, 98%, 15.4% and 98.7% for both. In cases with increased NT, the percentage of live births with normal karyotype and no major fetal structural defects decreased from 93.8% in normal DV-FVW fetuses to 77.3% in abnormal ones. CONCLUSION: DV assessment at 11-14 weeks' gestation is useful in screening for fetal chromosomal abnormalities and may help to reduce the false-positive rate when combined with NT measurement. Abnormal DV-FVW is also associated with an increase in adverse perinatal outcome in fetuses with enlarged NT. However, the value of DV-FVW assessment in cases with normal NT is unclear.     

Orbital apex osteodural fistula - An unusual surgical access

Dural arteriovenous fistulas (DAVFs) are fistulas connecting the branches of dural arteries to dural veins or a venous sinus. Osteodural fistulas are a rare subset of this group of diseases. We wish to report a rare case of an osteodural arteriovenous fistula at the foot of the superior ophthalmic vein (SOV), treatment of which required an unusual surgical approach via the orbit and SOV. Though access for endovascular treatment via the SOV for treatment of caroticocavernous fistulas is reported, the external approach is relatively infrequently performed, outside Europe and the Americas, with this being the first reported procedure from the Indian subcontinent. We wish to explain the steps of this unusual surgical access and highlight the salient precautions and pitfalls in the technique.     

Kinetics of peripheral blood mononuclear cell mobilization with chemotherapy and/or granulocyte-colony-stimulating factor: implications for yield of hematopoietic progenitor cell collections

BACKGROUND: Peripheral blood progenitor cells (PBPCs) are commonly collected and used to reconstitute hematopoiesis after high-dose chemotherapy. However, strategies for optimal collection and assessment of leukapheresis components are not standardized. STUDY DESIGN and METHODS: Hematopoietic progenitor cell assays were performed on 369 leukapheresis components collected from 95 patients who had received doxorubicin-based chemotherapy and/or granulocyte-colony-stimulating factor (G-CSF). Precollection patient hematologic values, leukapheresis collection values, component hematopoietic progenitor cell assays, and patient outcome measures were summarized. The kinetics of mononuclear cell (MNC) and PBPC mobilization were assessed among four patient groups. RESULTS: Patient group was a significant predictor of the peripheral blood MNC count on the day of collection (p<0.0001), and that value was a significant predictor of granulocyte-macrophage– colony-forming unit (CFU-GM) yield (p<0.0001). This relationship between the peripheral blood MNC count on the day of collection and CFU- GM yield differed according to patient group (p<0.0001). CFU-GM made up a larger fraction of peripheral blood MNCs collected from patients who received chemotherapy plus G-CSF than collected from those who received G-CSF alone. Moreover, the peripheral blood MNC count and the corresponding CFU-GM yield increased significantly on consecutive days of collection in patient groups receiving chemotherapy and G-CSF but were unchanged or decreased in patients receiving G-CSF alone. CONCLUSION: The relationship between peripheral blood MNC count and leukapheresis component CFU-GM yield differed significantly between patients who received chemotherapy and G-CSF and those who received G- CSF alone for the mobilization of PBPCs. Patient peripheral blood MNC count and component CFU-GM yield are useful for both assessing and suggesting revisions to PBPC mobilization and collection strategies.     

Effect of exogenous surfactant on total respiratory system compliance

We measured total respiratory system compliance (Crs) before and after instilling 25 mg artificial surfactant in 1 ml saline down the endotracheal tube of preterm babies requiring resuscitation at birth, and compared results with data from 6 similar babies receiving saline only. Surfactant did not produce a significant improvement in Crs.     

Frequency of oral mucosa micronuclei in gas station operators after introducing methanol

Methanol has been proposed in different countries as an alternative automotive fuel to be used as an additive to, or replacement for, gasoline or ethanol. Utilization of methanol is increasing exposure to low levels of methanol vapors in the environment and more specifically in occupational settings such as gas stations. Pump operators are exposed to relatively high levels of fuel vapors, the consequences of which have not been fully examined. In this study, the micronucleus assay in squamous oral cells was performed on pump operators of 28 gas stations in three different periods in the city of S?o Paulo, Brazil. The frequency of micronuclei (MN) was evaluated before and 1 year after a mixed fuel called MEG, which contains 33% methanol, 60% ethanol and 7% gasoline, was introduced. The third evaluation, 3 years later, represents a period where the number of cars using alcohol fuel had decreased drastically and the pump operator exposure to MEG became very low. The frequency of MN observed in 76 employees in 1992 (mean = 3.62 +/- 0.39) was significantly increased (P < 0.001) as compared with 76 operators exposed in 1989 (mean = 1.41 +/- 0.26) and 129 exposed in 1995 (mean = 1.20 +/- 0.15). These differences were also significant when compared with control groups not exposed professionally to motor fuel. These findings could indicate a mutagenic hazard of the MEG occurring in those with occupational exposure.     

Lipid profile of patients with increased risk for cardiovascular events in daily clinical practice

Although there are specific guidelines regarding the treatment of dyslipidemia in highly risk patients, these recommendations are usually inadequately followed. The aim of this study is to investigate risk factors in patients with increased cardiovascular risk currently treated in Brazil and Venezuela. Medical charts of 412 patients were selected in 4 institutions. Patients were divided into groups according to the use of lipid-lowering drugs (LLD), particularly statins. Patients who did not use LLD showed higher levels of total cholesterol (p< 0.001), LDL cholesterol (p< 0,001) and HDL cholesterol (p< 0.001), besides lower levels of triglycerides (p< 0.001). The use of statins was associated with a decrease in levels of total cholesterol (from 251.0 +/- 40.0 to 196.0 +/- 46.0), LDL cholesterol (from 168.0 +/- 36.0 to 116.0 +/- 39.0), HDL cholesterol (from 51.0 +/- 46.0 to 46.0 +/- 12.0) and triglycerides (from 181.0 +/- 120.0 to 160.0 +/-79.0). Finally, only a small percentage of patients, even those under treatment with LLD, showed cholesterol levels according to currently available guidelines. Therefore, although the guidelines for the treatment of dyslipidemia are widely known, only a small percentage of patients achieve adequate levels of cholesterol. It is necessary to decrease lipid levels of these patients by increasing the dose of the statins or using a second drug.     

Changes in blood cell membrane properties in HIV type-1-infected patients

To evaluate the possible HIV-1 infection-induced changes in cell membrane properties and in calcium signaling, membrane fluidity, acetylcholinesterase (AChE, a glycosylphosphatidylinositol-anchored protein) activity, and intracellular calcium concentration ([Ca2(+)](int)) were evaluated in lymphocytes and erythrocytes of infected individuals, previous to their engagement in antiretroviral therapy. Membrane fluidity was assessed by fluorescence spectroscopy measurements, using the fluorescence probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-[4-(trimethylamino)-phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH). AChE activity was determined by the colorimetric Ellman's method and [Ca2(+)](int) using the fluorescent fura-2 acetoxymethyl ester. When compared with the control group, lymphocytes of infected patients presented significantly decreased membrane fluidity, decreased AChE activity, and increased [Ca2(+)](int). Erythrocytes from HIV-infected patients presented decreased [Ca2(+)](int) when compared with the control group and decreased membrane fluidity near the lipid/water interface. Our data show that HIV-1 infection leads to biochemical and biophysical changes in the membrane itself and in membrane protein activity in lymphocytes (average of infected and noninfected subpopulations) and even in erythrocytes. The present observations are in agreement with a process of facilitated propagation of the infection to new cells, stimulation of virion production, and maintenance of a reservoir of erythrocyte-bound infectious virus.