Citations

Background— Monocyte chemoattractant proteins (MCPs) play an important role in mediating inflammatory processes. Hypertension (HTN) is associated with inflammation as well as impaired cardiac microcirculatory function and structure, but the contribution of MCPs to these alterations remained unclear. This study tested the hypothesis that MCPs regulate cardiac microvascular function and structure in experimental HTN. Methods and Results— Pigs (n=6 per group) were studied after 10 weeks of normal, renovascular HTN, or renovascular HTN+ bindarit (MCPs inhibitor, 50 mg/kg/d PO). Left ventricular (LV) function, myocardial microvascular permeability, and fractional vascular volume were assessed by fast computed tomography before and after adenosine infusion (400 μg/kg/min). Myocardial fibrosis, inflammation, and microvascular remodeling were determined ex vivo. Hypertension was not altered by bindarit, but LV hypertrophy and diastolic function were improved. In response to adenosine, myocardial microvascular permeability increased in HTN (from 0.0083±0.0009 to 0.0103±0.0011 AU, P =0.038 versus baseline) and fractional vascular volume decreased, whereas both remained unchanged in normal and HTN+bindarit pigs. HTN upregulated endothelin-1 expression, myocardial inflammation, and microvascular wall thickening, which were inhibited by bindarit. Conclusions— MCPs partly mediate myocardial inflammation, fibrosis, vascular remodeling, and impaired vascular integrity induced by hypertension. Inhibition of MCPs could potentially be a therapeutic target in hypertensive cardiomyopathy.

Objective: To describe a case of acquired Fanconi syndrome after treatment with capecitabine, irinotecan, and bevacizumab. Case Summary: A 77-year-old female with metastatic colon cancer presented with vomiting and diarrhea. The patient had been diagnosed with stage IIIC (T3, N2, M0) colon cancer 18 months earlier and was initially treated with FOLFOX6 (regimen of oxaliplatin, fluorouracil, and leucovorin) after her hemicolectomy. She was switched to a capecitabine/oxaliplatin regimen after 4 cycles due to central access problems. She did well until 10 months after her cancer diagnosis, when metastasis was discovered. She was started on reduced doses of capecitabine, irinotecan, and bevacizumab. After her eleventh cycle, she presented to the hospital with the above symptoms. Laboratory test results showed hypokalemia, hypocalcemia, hypophosphatemia, and hypouricemia. The patient had not been started on any new medications other than chemotherapy for over 1 year. The electrolyte derangements were new, since the patient had laboratory values checked every 3 weeks. Despite daily intravenous replacements, the electrolyte abnormalities persisted. Laboratory evaluations demonstrated the presence of euglycemic glucosuria and a high fractional excretion of phosphorus in the setting of hypophosphatemia. Fanconi syndrome was confirmed by demonstration of aminoaciduria. Discussion: Fanconi syndrome is a disorder characterized by proximal tubular dysfunction resulting in electrolyte wasting. In the acquired form, medications and multiple myeloma are the most common causes. Based on the Naranjo probability scale, a drug was the probable cause of Fanconi syndrome in our patient. However, because multiple drugs were involved, it was not possible to determine which one was the culprit. Conclusions: This is the first case of Fanconi syndrome reported after the administration of capecitabine, irinotecan, and bevacizumab. More studies are needed to confirm this association.

Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.

Abstract Microcephalin (MCPH1) is a BRCA1 COOH terminal (BRCT) domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double-strand breaks by phosphorylated histone H2AX (γH2AX), but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here, we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the NH2 terminus of BRCA2 and the COOH terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double-strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51-dependent and BRCA2-dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double-stand breaks. [Cancer Res 2009;69(13):5531–6]

Background: Intravenous sodium bicarbonate (SB) administration during cardiopulmonary arrest (CPA) is intended to counteract lactic acidosis due to hypoxia, poor perfusion, and anaerobic metabolism. Despite a lack of documented efficacy and a level III recommendation from the American Heart Association, SB is widely used during resuscitation events. SB has both theoretical and measurable adverse effects. Excess or poorly timed administration during a CPA may elevate a patient's pH, inducing alkalemia. Despite decades of controversy surrounding use of this drug, the prevalence of SB-induced alkalemia has not been previously documented. Objective: To estimate the prevalence of SB-induced alkalemia in inpatients after CPA and to investigate the pattern of SB administration. Methods: Medical records were retrospectively reviewed with attention to SB administration and arterial blood gas (ABG) data. After application of inclusion and exclusion criteria to 264 CPA patients, the study group comprised 88 patients. When measured, il PCO 2 and pH were above normal limits after SB administration, we concluded that SB contributed to the alkalemia. Results: Twenty-seven (31 %) patients received SB without any ABG data, and 70 (79%) patients received at least one empiric SB dose. Of the 61 patients with ABG data, alkalemia occurred in 10, a prevalence of 16%. Administration of SB increased pH in only 9 (15%) other CPA patients and had no effect in the 42 (69%) remaining patients. Conclusions: Administration of SB during CPA was causally linked with inducing alkalemia in 16% of patients. Early collection of ABG samples may assist in optimizing pH during CPA and thus reduce unwarranted empiric use of SB.