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.     

Neurotoxicity of FIV and FIV envelope protein in feline cortical cultures

The neurotoxic effects of the feline immunodeficiency virus (FIV) and FIV envelope proteins were measured in primary cultures of feline cortical neurons. Envelope protein from the FIV-PPR strain promoted neuronal swelling and death, whereas envelope protein from the FIV-34TF10 isolate produced intermediate or negligible toxicity. No effect was observed in control cultures treated with envelope protein from the Epstein–Barr virus. A concentration–effect curve showed that FIV-PPR protein produced maximal toxicity at 200 pM protein and decreased toxicity at higher concentrations, which is consistent with previous reports of the HIV-1 surface glycoprotein, gp120. These effects required the presence of low concentrations of glutamate. Using the natural host cells as targets, the effects of envelope protein and infectious virions were directly compared. All of the toxic activity could be attributed to non-infectious interactions between the viral envelope and target cells. Addition of 1 μM tetrodotoxin failed to block the effects of FIV-PPR in the presence of 20 μM glutamate. Toxicity would appear to involve two steps in which the envelope protein first sensitizes neurons through non-synaptic interactions (TTX insensitive) thereby setting the stage for enhanced synaptic activation via glutamate receptors (TTX sensitive).     

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.     

Leptospirosis among patients presenting with dengue-like illness in Puerto Rico

Leptospirosis is difficult to distinguish from dengue fever without laboratory confirmation. Sporadic cases/clusters of leptospirosis occur in Puerto Rico, but surveillance is passive and laboratory confirmation is rare. We tested for leptospirosis using an IgM ELISA on sera testing negative for dengue virus IgM antibody and conducted a case-control study assessing risk factors for leptospirosis, comparing clinical/laboratory findings between leptospirosis (case-patients) and dengue patients (controls). Among 730 dengue-negative sera, 36 (5%) were positive for leptospirosis. We performed post mortem testing for leptospirosis on 12 available specimens from suspected dengue-related fatalities; 10 (83%) tested positive. Among these 10 fatal cases, pulmonary hemorrhage and renal failure were the most common causes of death. We enrolled 42 case-patients and 84 controls. Jaundice, elevated BUN, hyperbilirubinemia, anemia, and leukocytosis were associated with leptospirosis (p < .01 for all). Male sex, walking in puddles, rural habitation, and owning horses were independently associated with leptospirosis. Epidemiological, clinical, and laboratory criteria may help distinguish leptospirosis from dengue and identify patients who would benefit from early antibiotic treatment.     

Low–Molecular-Weight-Heparins as Periprocedural Anticoagulation for Patients on Long-Term Warfarin Therapy: A Standardized Bridging Therapy Protocol

Background: Over 2 million patients in North America are on warfarin anticoagulation therapy for prevention of thromboembolism. Suspension of warfarin therapy is often required to prepare patients for invasive procedures or surgeries. To protect these patients against thromboembolism while they are off warfarin, shorter-acting parenteral agents such as low-molecular-weight heparins (LMWHs) are often used. We conducted a retrospective observational study of our anticoagulation clinic patients to assess the safety and efficacy of LMWHs using a standardized protocol for periprocedural anticoagulation therapy.Methods: We included 69 consecutive patients who required interruption of their long-term warfarin therapy between August 2001 and August 2002, and were deemed by the treating physician to be at high enough risk for perioperative thromboembolism to justify bridging anticoagulation. We used a standard bridging therapy protocol in our anticoagulation clinic. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death.Results: There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.Conclusions: LMWH administration using our standard outpatient bridging protocol for perioperative anticoagulation appears to be relatively safe and efficacious, offering an alternative to inpatient administration of intravenous unfractionated heparin (UFH). Our study provides additional evidence to the limited published observational data regarding the safety and efficacy of LMWH as bridging therapy in the perioperative and periprocedural setting. Large, multicenter, randomized controlled trials are necessary to fully assess the safety and efficacy of LMWH for perioperative anticoagulation.Abbreviated Abstract We conducted a retrospective observational study of 69 consecutive anticoagulation clinic patients on warfarin between August 2001 and August 2002, who were undergoing a procedure or surgery. The study was done to assess the safety and efficacy of an outpatient LMWH bridging protocol. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 3 days preoperatively and 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death. There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.     

The Training of Geriatricians in the United States: Three Decades of Progress

During the past 3 decades, significant progress has been made in preparing U.S. physicians to care for the growing elderly population. This paper reviews progress in training and certifying internists and family physicians in geriatric medicine. The establishment of the National Institute on Aging, a series of Institute of Medicine reports, Veterans Health Administration initiatives, and leadership and investment by the public sector and private foundations have supported the development of geriatric medicine training programs. In 1988, the Accreditation Council for Graduate Medical Education initially accredited 62 internal medicine (IM) and 16 family practice (FP) geriatric medicine fellowship programs. By academic year 2001–2002, 120 geriatric medicine fellowships were training 338 fellows. A recent survey of U.S. medical schools found a total of 869 full-time equivalent (FTE) geriatrics faculty members. Their geriatrics programs had a median of 5.0 FTE physician faculty members, with a range of 0 to 42. Recent surveys of IM and FP residency programs found 803 geriatrician faculty members teaching in IM residency programs (53% response rate) and 453 teaching in FP residency programs (75% response rate). From 1988 through 2002, 10,207 Certificates of Added Qualifications in Geriatrics were awarded. The distribution of these practicing geriatricians varied considerably by state, with the national average being 5.5 per 10,000 persons aged 75 and older. Individual state rates ranged from 2.2 to 15.9. Although geriatric medicine training has grown remarkably over the past 3 decades, this growth is still not producing the number of geriatricians needed to care for the growing elderly population. Thus, expanded investment in the training of geriatricians as faculty and practitioners is needed.