Serum anti-GM2 and anti-GalNAc-GD1a IgG antibodies are biomarkers for acute canine polyradiculoneuritis.

OBJECTIVES: A previous single-country pilot study indicated serum anti-GM2 and anti-GA1 anti-glycolipid antibodies as potential biomarkers for acute canine polyradiculoneuritis. This study aims to validate these findings in a large geographically heterogenous cohort. MATERIALS AND METHODS: Sera from 175 dogs clinically diagnosed with acute canine polyradiculoneuritis, 112 dogs with other peripheral nerve, cranial nerve or neuromuscular disorders and 226 neurologically normal dogs were screened for anti-glycolipid antibodies against 11 common glycolipid targets to determine the immunoglobulin G anti-glycolipid antibodies with the highest combined sensitivity and specificity for acute canine polyradiculoneuritis. RESULTS: Anti-GM2 anti-glycolipid antibodies reached the highest combined sensitivity and specificity (sensitivity: 65.1%, 95% confidence interval 57.6 to 72.2%; specificity: 90.2%, 95% confidence interval 83.1 to 95.0%), followed by anti-GalNAc-GD1a anti-glycolipid antibodies (sensitivity: 61.7%, 95% confidence interval 54.1 to 68.9%; specificity: 89.3%, 95% confidence interval 82.0 to 94.3%) and these anti-glycolipid antibodies were frequently present concomitantly. Anti-GA1 anti-glycolipid antibodies were detected in both acute canine polyradiculoneuritis and control animals. Both for anti-GM2 and anti-GalNAc-GD1a anti-glycolipid antibodies, sex was found a significantly associated factor with a female to male odds ratio of 2.55 (1.27 to 5.31) and 3.00 (1.22 to 7.89), respectively. Anti-GalNAc-GD1a anti-glycolipid antibodies were more commonly observed in dogs unable to walk (OR 4.56, 1.56 to 14.87). CLINICAL SIGNIFICANCE: Anti-GM2 and anti-GalNAc-GD1a immunoglobulin G anti-glycolipid antibodies represent serum biomarkers for acute canine polyradiculoneuritis.

Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis.

There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type IQSEC2 led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of Iqsec2 were recapitulated in neurons from Iqsec2 knockout mice generated in our laboratory using CRISPR/Cas9 technology. These observations provide evidence of dosage sensitivity for IQSEC2, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.

Advances in anticancer radiopharmaceuticals.

This review highlights recent progress in the development of anticancer radiopharmaceuticals. Molecularly targeted radiotherapy refers to the selective delivery of radionuclides that emit charged particles, such as α particles, ß or Auger electrons, to cancer cells via a targeting vector. The discovery of new molecular targets through systems biology and other approaches has widened the scope for radiopharmaceutical development. Innovations in antibody engineering and humanisation, recombinant DNA technology, conjugation chemistry and, increasingly, nanotechnology have provided new approaches to the delivery of radionuclides to cancer cells. The increased availability of radioisotopes that have not traditionally been considered for therapy, such as α particle emitters, has also broadened the indications for targeted radiotherapy.

Analyses of eutectoid phase transformations in Nb-silicide in situ composites.

Nb-silicide in situ composites have great potential for high-temperature turbine applications. Nb-silicide composites consist of a ductile Nb-based solid solution together with high-strength silicides, such as Nb5Si3 and Nb3Si. With the appropriate addition of alloying elements, such as Ti, Hf, Cr, and Al, it is possible to achieve a promising balance of room-temperature fracture toughness, high-temperature creep performance, and oxidation resistance. In Nb-silicide composites generated from metal-rich binary Nb-Si alloys, Nb3Si is unstable and experiences eutectoid decomposition to Nb and Nb5Si3. At high Ti concentrations, Nb3Si is stabilized to room temperature, and the eutectoid decomposition is suppressed. However, the effect of both Ti and Hf additions in quaternary alloys has not been investigated previously. The present article describes the discovery of a low-temperature eutectoid phase transformation during which (Nb)3Si decomposes into (Nb) and (Nb)5Si3, where the (Nb)5Si3 possesses the hP16 crystal structure, as opposed to the tI32 crystal structure observed in binary Nb5Si3. The Ti and Hf concentrations were adjusted over the ranges of 21 to 33 (at.%) and 7.5 to 33 (at.%) to understand the effect of bulk composition on the phases present and the eutectoid phase transformation.

Accurate power approximations for chi2-tests in case-control association studies of complex disease genes.

A popular method for the analysis of case-control association studies is to compare the frequencies of the alleles between cases and controls by means of Pearson's chi2-statistic. Here, an approach for computing the power of this test is presented, which by computer simulation is shown to be more reliable than a previously published power approximation. Since the test based on Pearson's chi2- statistic can be anti-conservative if there is an excess of homozygotes for the susceptibility allele in the general population, it has been proposed to analyze case-control association studies by means of a trend test based on genotypes instead of alleles. We present an accurate power approximation for the trend test. The power approximations are implemented in an available computer program 'GenOdyPower', which in addition has an option to determine the empirical power of these tests by simulations.

The clinical course of new-onset atrial fibrillation after elective aortic operations.

BACKGROUND: The onset of atrial fibrillation (AFIB) in the postoperative setting has been associated with increased morbidity and mortality in patients undergoing major noncardiothoracic operations. The purpose of this study was to determine the incidence, associated complications, and outcomes of AFIB after open aortic operations. STUDY DESIGN: We studied 211 consecutive patients undergoing elective aortic operations at a single hospital during a recent 6-year period. Postoperatively all patients had continuous ECG monitoring in the ICU for a mean (+/- SD) of 6 +/- 8 days and routine cardiac enzyme determinations. RESULTS: AFIB developed in 22 of the 211 patients (10%), a mean (+/- SD) of 2 +/- 1 days after operation, and it lasted for a mean of 4 +/- 6 days after onset. Sixteen patients spontaneously reverted to normal sinus rhythm, 3 required cardioversion (2 chemical, 1 electrical), and 3 continued in AFIB at discharge. Four of the 22 patients suffered additional cardiac complications, including antecedent MI in 3 (14%) and sustained cardiogenic shock requiring electrical cardioversion in 1. By comparison, the incidence of MI in the other 189 patients was 4% (no significant difference [NSD]). There were no deaths in the AFIB patients. Cardiac emboli developed in none of the 22 patients, and all patients had normal sinus rhythm on ECG obtained a mean of 14 +/- 10 months after discharge. Comparing the 22 patients with AFIB with the 189 patients without AFIB, there were no differences in the mean duration of ICU stay (6 +/- 4 versus 6 +/- 8 days), total length of hospital stay (10 +/- 5 versus 11 +/- 10 days), or hospital mortality (0% versus 0.5%). AFIB patients were older (71 versus 66 years, p = 0.016), but there was no difference in gender or use of beta-blockers between the two groups. CONCLUSIONS: These data suggest that AFIB is not uncommon after aortic operations but is not associated with increased morbidity, mortality, or length of hospital stay. Although a minority of affected patients can have other cardiac complications such as MI, these complications are usually recognized before the onset of AFIB. AFIB does not affect the outcomes of aortic operations. Most patients will revert spontaneously to normal sinus rhythm and do not require longterm anticoagulation to prevent thromboembolic complications.

Fibrin sealants in surgical practice: An overview.

The need to effectively manage hemostasis and tissue sealing during surgery has had a strong influence on the development of modern surgical techniques. A group of agents known as surgical tissue adhesives has been developed to promote hemostasis and tissue sealing during surgery, and these comprise both natural and synthetic agents. Fibrin sealants are the most effective tissue adhesives currently available, and they are biocompatible and biodegradable. The fibrin sealants are comprised of purified, virus-inactivated human fibrinogen, human thrombin, and sometimes added components, such as virus-inactivated human factor XIII and bovine aprotinin. These agents mimic the final steps of the physiological coagulation cascade to form a fibrin clot. The use of any plasma-derived product in the surgical setting carries a potential risk of viral transmission. In fact, it was the risk of viral transmission from fibrinogen and thrombin that halted development work on fibrin sealants in the United States. Since that time, new techniques for isolating and concentrating plasma fractions have been developed, and national and international guidelines have been introduced to ensure the safety of all plasma products. All plasma donors are carefully selected and their plasma units screened for viral contamination before processing. All plasma donations and bovine tissue used in the production of commercial fibrin sealants undergo rigorous viral reduction/elimination steps. As a result of this carefully controlled and monitored process, there have been no proven cases of viral transmission associated with the use of commercial fibrin sealant. Fibrin sealants are currently used in a number of surgical specialties, including cardiovascular surgery, thoracic surgery, neurosurgery, plastic and reconstructive surgery, and dental surgery. The use of fibrin sealants has a positive effect on surgical outcomes, such as improved time to hemostasis, reduced blood loss, and reduced complications. This review describes the development of fibrin sealants, the composition of currently available products, and their use in surgical practice.

New and potential uses of fibrin sealants as an adjunct to surgical hemostasis.

Commercially prepared fibrin sealants have been available in Europe and Japan for many years. However, current formulations are exclusively two-component, liquid fibrin sealants, and delivery devices are rather rudimentary. To date, this has had the effect of limiting the number of clinical applications that make use of fibrin sealants. The recent licensing of fibrin sealants by the Food and Drug Administration in the United States has the potential to expand the use of these products in established procedures. As surgeons gain experience with fibrin sealants, it is likely that new clinical applications will be developed in a wider range of surgical specialties. The aim of this article is to explore the potential future formulations and uses of fibrin sealants and highlight a range of surgical procedures that may benefit from these products.

Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B.

Human cytomegalovirus (HCMV) infection alters the expression of many cellular genes, including IFN-stimulated genes (ISGs) [Zhu, H., Cong, J.-P., Mamtora, G., Gingeras, T. & Shenk, T. (1998) Proc. Natl. Acad. Sci. USA 95, 14470-14475]. By using high-density cDNA microarrays, we show that the HCMV-regulated gene expression profile in fibroblasts does not differ substantially from the response generated by IFN. Furthermore, we identified the specific viral component triggering this response as the envelope glycoprotein B (gB). Cells treated with gB, but not other herpesviral glycoproteins, exhibited the same transcriptional profile as HCMV-infected cells. Thus, the interaction of gB with its as yet unidentified cellular receptor is the principal mechanism by which HCMV alters cellular gene expression early during infection. These findings highlight a pioneering paradigm for the consequences of virus-receptor interactions.

The crystal structures of K(bm1) and K(bm8) reveal that subtle changes in the peptide environment impact thermostability and alloreactivity.

The K(bm1) and K(bm8) natural mutants of the murine MHC class I molecule H-2K(b) were originally identified by allograft rejection. They also bind viral peptides VSV8 and SEV9 with high affinity, but their peptide complexes have substantially decreased thermostability, and the K(bm1) complexes do not elicit alloreactive T cell responses. Crystal structures of the four mutant complexes at 1.7-1.9 A resolution are similar to the corresponding wild-type K(b) structures, except in the vicinity of the mutated residues, which alter the electrostatic potential, topology, hydrogen bonding, and local water structure of the peptide binding groove. Thus, these natural K(b) mutations define the minimal perturbations in the peptide environment that alter antigen presentation to T cells and abolish alloreactivity.

The use of lepirudin for anticoagulation in patients with heparin-induced thrombocytopenia during major vascular surgery.

The method of anticoagulation in patients undergoing major vascular surgery with a history of heparin-induced thrombocytopenia (HIT) is controversial. We present two cases in which a bolus only technique using recombinant hirudin (Lepirudin or Refludan) was used successfully in patients with HIT scheduled for vascular surgery.

Repair of a saccular aortic aneurysm with superficial femoral-popliteal vein in the presence of a pancreatic abscess.

When one is faced with impending rupture, repair of an aortic aneurysm cannot be delayed. In the presence of coexisting intra-abdominal sepsis, traditional therapy would call for aneurysm exclusion and axillofemoral bypass grafting. Consequences of this choice of treatment include limited long-term graft patency and recurrent prosthetic infection. Autogenous deep veins from the lower extremities have demonstrated exceptional patency and resilience to infection when used to replace infected aortic grafts. We now report a case of concomitant open drainage of a pancreatic abscess and repair of a saccular abdominal aortic aneurysm using the superficial femoral-popliteal vein as a conduit.

Effect of early maternal iron stores on placental weight and structure.

BACKGROUND: Large placental size and low birthweight have been implicated as factors predicting high blood pressure in adulthood. Maternal anaemia has been suggested as a link. We investigated the interaction between maternal iron status and other factors known to influence birthweight and placental size. METHODS: In a prospective study of 1650 low-risk, singleton, caucasian pregnancies, we related placental size and birthweight to maternal iron status, socioeconomic status, and parity. Placental morphology was assessed in 17 randomly chosen primigravid pregnancies. FINDINGS: Parity was an important determinant of birthweight (mean standard deviation score -0.13 [SD 0.90] para 0; -0.24 [0.90] para 1; 0.32 [1.1] para 2; 0.21 [1.1] para > or = 3; p<0.0001) and placental weight (mean 655 g [SD 130]; 679 g [122]; 675 g [139]; 694 g [157], respectively; p=0.01). Cigarette smoking influenced birthweight only. Socioeconomic status had little effect after correction for parity. In addition to parity, the factors influencing placental weight were maternal height, weight, and serum ferritin concentration at booking, but not haemoglobin concentration. Serum ferritin concentrations were associated with folate intake and parity. In the placental morphology subset, serum ferritin concentration was inversely related to overall measures of peripheral villous capillarization. Haemoglobin concentration showed no such association. INTERPRETATION: These findings show a relation between maternal anaemia and placental size and birthweight across the normal range for these measures. Low ferritin concentrations in early pregnancy were associated with increased placental vascularisation at term. The association between ferritin concentration and folate supplementation emphasises the importance of preconceptional health, particularly in women at high risk of iron deficiency.

Acute pancreatitis after abdominal vascular surgery.

BACKGROUND: Retroperitoneal dissection and ischemia have been proposed as risk factors for postoperative pancreatitis. Although both are routine components of abdominal vascular operations, postoperative pancreatitis has not been adequately evaluated in vascular patients. The purpose of this study was to determine the incidence and outcomes of pancreatitis after abdominal vascular surgery. STUDY DESIGN: We collected pre-, intra-, and postoperative data on 21 patients who developed pancreatitis after abdominal vascular operations. For comparison, we studied 21 age- and gender-matched case controls undergoing identical operations during the same period. RESULTS: The incidence of pancreatitis among all patients undergoing abdominal vascular operations during the 6-year study period was 1.8%. Pancreatitis was diagnosed 9.8 +/- 8 days after operation and was associated with 3 or less Ranson signs in all 21 study subjects. The following outcomes data differed between the two groups: duration of npo (9 +/- 6 days for subjects versus 3.9 +/- 2 days for controls, p < 0.001) and need for parenteral nutrition (13 subjects versus no controls, p < 0.00 1). Although there was a trend towards longer hospitalization in the subjects (16 +/- 12 days versus 11 +/- 8 days, p = 0.08), there was no difference in complication rates between the two groups. Sixteen subjects (76%) had no complications. Three developed severe complications, two of whom died of causes unrelated to pancreatitis. One developed a pseudocyst that resolved spontaneously. Cholelithiasis was a causative factor in 2 subjects; no cause was established in the remaining 19. There was no difference in operative details between the two groups. CONCLUSIONS: These data indicate that pancreatitis is a rare and self-limited complication of abdominal vascular surgery. Our findings suggest that pancreatitis is costly and inconvenient but rarely serious after abdominal vascular operations.

Watchful waiting in cases of small abdominal aortic aneurysms- appropriate for all patients?

OBJECTIVE: The purpose of this study was to determine the effect of patient compliance on a program of watchful waiting in cases of small abdominal aortic aneurysms and to document the proportion of patients who become prohibitive operative risks during follow-up. STUDY DESIGN: A retrospective review was conducted at a regional military veterans medical center. The subjects were 101 male military veterans with abdominal aortic aneurysms measuring less than 5 cm who did not have medical contraindications to operative repair. The main outcome measures were (1) the proportion of patients who missed three scheduled radiologic tests in a row despite written notifications mailed to their homes and (2) the proportion of compliant patients who had medical illnesses and became prohibitive operative risks during follow-up. RESULTS: During a follow-up (mean +/- SEM) of 34 +/- 2 months, 69 patients (69%) were fully compliant with the watchful waiting program and underwent a mean of 4.5 +/- 0.3 radiologic tests. There were no abdominal aortic aneurysm ruptures in this subgroup. Twenty-five patients (36%) had indications for abdominal aortic aneurysm repair, and 28 (41%) have not met the criteria for repair. Sixteen (23%) of the 69 compliant patients developed prohibitive medical risks during follow-up; eight (50%) of these 16 patients died, all of the causes unrelated to their abdominal aortic aneurysms. Thirty-two (32%) of the 101 study subjects were noncompliant with the watchful waiting program. Twenty-seven (84%) of the noncompliant patients did not keep any scheduled appointments, and five (16%) were lost after one or two examinations. Three of the noncompliant patients experienced documented abdominal aortic aneurysm rupture, and it is suspected in a fourth. Direct contact was made with 28 (88%) of these patients or their families; all acknowledged having received written notifications regarding their watchful waiting program tests and had decided not to continue with surveillance for a variety of socioeconomic reasons. Between the 69 compliant patients and the 32 noncompliant patients, there were no differences with respect to mean age (70 +/- 1 years vs 73 +/- 2 years), distance from home of record to the hospital (62 +/- 14 miles vs 73 +/- 23 miles), or abdominal aortic aneurysm size at initial detection (3.75 +/- 0.5 cm vs 3.8 +/- 0.5 cm). CONCLUSIONS: Watchful waiting programs are imperfect and highly reliant on the motivation levels and means of the individual patients. Watchful waiting is reasonable among compliant patients with abdominal aortic aneurysms, inasmuch as fewer than half will meet the criteria for intervention within a mean of 3 years. Approximately one fourth of these patients will have medical contraindications to abdominal aortic aneurysm repair during follow-up, and many of these will die of causes other than abdominal aortic aneurysm rupture. In our experience, one third of candidates for watchful waiting programs are unable to participate and are at risk of rupture. These patients need special attention so that the reasons for their noncompliance can be determined, and they may be candidates for earlier intervention.