Breast Cancer and Non‐Hodgkin Lymphoma in a Young Male with Cowden Syndrome

Male breast cancer (MBC) is unusual, especially in young adults. Most cases of MBC as a secondary malignancy relate to the previous treatment with ionizing radiation. MBC can be associated with mutations in hereditary cancer predisposition syndrome genes (i.e., BRCA2); however, no such association has been reported in patients with Cowden syndrome (involving the phosphatase and tensin homolog [PTEN] gene). We describe a patient with Cowden syndrome who was initially diagnosed with B‐cell lymphoblastic lymphoma at the age of 7 years, then MBC at the age of 31 years, and never received radiation therapy.     

Trauma Whipple: Do or Don’t After Severe Pancreaticoduodenal Injuries? An Analysis of the National Trauma Data Bank (NTDB)

Background

Pancreaticoduodenectomy for trauma (PDT) is a rare procedure, reserved for severe pancreaticoduodenal injuries. Using the National Trauma Data Bank (NTDB), our aim was to compare outcomes of PDT patients to similarly injured patients who did not undergo a PDT.

Methods

Patients with pancreatic or duodenal injuries treated with PDT (ICD-9-CM 52.7) were identified in the NTDB 2008–2010 Research Data Sets. We excluded those who underwent delayed PDT (>4 days). The PDT group (n = 39) was compared to patients with severe combined pancreaticoduodenal injuries (grade 4 or 5) who did not undergo PDT (non-PDT group, n = 38). Patients who died in the emergency department or did not undergo a laparotomy were excluded. Our primary outcome was death. Secondary outcomes were intensive care unit length of stay (LOS), hospital LOS, and total ventilator days. A multivariate model was used to determine predictors of in-hospital mortality within each group and in the overall cohort.

Results

The non-PDT group had a significantly lower systolic blood pressure and Glasgow Coma Scale values at baseline and more severe duodenal, pancreatic, and liver injuries. There were no significant differences in outcomes between the two groups. The Injury Severity Score was the only independent predictor of mortality among PDT patients [odds ratio (OR) 1.12, 95 % confidence interval (CI) 1.01–1.24] and in the entire cohort (OR 1.06, 95 % CI 1.01–1.12). The operative technique did not influence any of the outcomes.

Conclusions

Compared to non-PDT, PDT did not result in improved outcomes despite a lower physiologic burden among PDT patients. More conservative procedures for high-grade injuries of the pancreaticoduodenal complex may be appropriate.     

Investigating the role of DNA damage in tobacco smoking-induced spine degeneration

Background contextTobacco smoking is a key risk factor for spine degeneration. However, the underlying mechanism by which smoking induces degeneration is not known. Recent studies implicate DNA damage as a cause of spine and intervertebral disc degeneration. Because tobacco smoke contains many genotoxins, we hypothesized that tobacco smoking promotes spine degeneration by inducing cellular DNA damage.PurposeTo determine if DNA damage plays a causal role in smoking-induced spine degeneration.Study designTo compare the effect of chronic tobacco smoke inhalation on intervertebral disc and vertebral bone in normal and DNA repair-deficient mice to determine the contribution of DNA damage to degenerative changes.MethodsTwo-month-old wild-type (C57BL/6) and DNA repair-deficient Ercc1^?/Δ mice were exposed to tobacco smoke by direct inhalation (4 cigarettes/day, 5 days/week for 7 weeks) to model first-hand smoking in humans. Total disc proteoglycan (PG) content (1,9-dimethylmethylene blue assay), PG synthesis (³⁵S-sulfate incorporation assay), aggrecan proteolysis (immunoblotting analysis), and vertebral bone morphology (microcomputed tomography) were measured.ResultsExposure of wild-type mice to tobacco smoke led to a 19% increase in vertebral porosity and a 61% decrease in trabecular bone volume. Intervertebral discs of smoke-exposed animals also showed a 2.6-fold decrease in GAG content and an 8.1-fold decrease in new PG synthesis. These smoking-induced degenerative changes were similar but not worse in Ercc1^?/Δ mice.ConclusionsShort-term exposure to high levels of primary tobacco smoke inhalation promotes degeneration of vertebral bone and discs. Disc degeneration is primarily driven by reduced synthesis of proteoglycans needed for vertebral cushioning. Degeneration was not exacerbated in congenic DNA repair-deficient mice, indicating that DNA damage per se does not have a significant causal role in driving smoke-induced spine degeneration.     

Increased risk of cardiovascular perforation during ECMO with a bicaval,wire-reinforced cannula

Purpose

Cardiac or major vascular perforation is a rare but serious risk of ECMO. We sought to determine if perforation rates are related to cannula design.

Methods

We utilized three methods to evaluate perforation on ECMO. 1. The ELSO registry was queried to establish the historical rate of hemorrhagic pericardial tamponade. 2. ELSO centers were surveyed regarding cannula related perforation events and brands of cannulas used over a four year time period (January 2008–March 2012). 3. The FDA’s MAUDE database was reviewed looking for adverse events related to ECMO cannulas.

Results

The historical rate of hemorrhagic pericardial tamponade in the ELSO registry was 0.53% (~ 1985–2010, ELSO registry). In the survey there were eleven reports of cannula-related perforation, 0.74% (11/1482 p-value = 0.29) at 7 different ELSO centers with 23 ELSO centers responding (17% response rate). The incidence of perforation was much higher for the wire-reinforced bicaval design 3.6% (10/279) as compared to catheters designed for the atrial position, 0.1% (1/1203, p-value < 0.0001). Review of the FDA’s MAUDE database revealed 19 adverse events related to the bicaval cannula design, 16 of which were hemorrhagic pericardial effusions or tamponade.

Conclusion

These findings suggest a relatively high rate of cardiac perforation associated with the dual lumen bicaval cannula. This may be related to inherent differences in cannula design or the IVC positioning required by the design.     

Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection

Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies (bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.Seasonal influenza outbreaks across the globe cause an estimated 250,000–500,000 deaths annually (1). Current influenza vaccines need to be updated every few years because of antigenic drift (2). Despite intensive monitoring, strain mismatch between vaccine formulation and influenza viruses circulating within the population has occurred in the past (2). Public health is further compromised when an unpredictable mixing event among influenza virus genomes leads to antigenic shift facilitating a potential pandemic outbreak. These concerns have expedited efforts toward developing a universal influenza vaccine.Neutralizing antibodies (nAbs) against hemagglutinin (HA) are the primary correlate for protection in humans and hence HA is an attractive target for vaccine development (3). The precursor polypeptide, HA0, is assembled into a trimer along the secretory pathway and transported to the cell surface. Cleavage of HA0 generates the disulfide-linked HA1 and HA2 subunits. Mature HA has a globular head domain which mediates receptor binding and is primarily composed of the HA1 subunit, whereas the stem domain predominantly comprises the HA2 subunit. The HA stem is trapped in a metastable state and undergoes an extensive low-pH-induced conformational rearrangement in the host-cell endosomes to adopt the virus–host membrane fusion-competent state (4, 5).The antigenic sites on the globular head of HA are subjected to heightened immune pressure resulting in escape variants, thereby limiting the breadth of head-directed nAbs (6). However, extensive efforts have resulted in the isolation of monoclonal antibodies (mAbs) that bind within the globular head and inhibit receptor attachment, which neutralize drifted variants of an HA subtype or heterosubtypic HA (7–16). The HA stem is targeted by several broadly neutralizing antibodies (bnAbs) with neutralizing activity against diverse influenza A virus subtypes (17). The epitopes of these bnAbs in the HA stem are more conserved across different influenza HA subtypes compared with the antigenic sites in the HA globular head (18).During a primary infection, the immunodominant globular head domain suppresses the response toward the conserved stem. Several efforts have been made to circumvent this problem. Repeated immunizations with full-length, chimeric HAs (cHAs) in a protracted vaccination regimen have been shown to boost stem-directed responses in mice (19). Alternatively, full-length HA presented on nanoparticles (np) has been shown to elicit stem-directed nAbs (20). Attempts have also been made to steer the immune response toward the conserved HA stem by hyperglycosylating the head domain (21). Although the aforementioned strategies need to be further evaluated and provide novel alternatives, detrimental interference from the highly variable immunodominant head domain in eliciting a broad functional response cannot be completely evaded. A “headless” stem domain immunogen offers an attractive solution. However, early attempts at expressing the HA2 subunit independently in a native, prefusion conformation were unsuccessful. In the absence of the head domain, the HA2 subunit expressed in Escherichia coli spontaneously adopted the low-pH conformation (22) in which the functional epitopes of stem-directed bnAbs are disrupted. More recently, the entire HA stem region has been expressed in a prefusion, native-like conformation in both prokaryotic and eukaryotic systems adopting multiple strategies (23–26).Design of independently folding HA stem fragments which adopt the prefusion HA conformation presents another approach to elicit bnAbs against influenza (27, 28). The A helix of the HA2 subunit contributes substantial contact surface to the epitope of stem-directed bnAbs such as CR6261, F10, and others. Although multivalent display of A helix on the flock house virus as a virus-like particle platform elicited cross-reactive antibodies, it conferred only minimal protection (20%) against virus challenge in mice (29).We report the design and characterization of engineered headless HA stem immunogens based on the influenza A/Puerto Rico/8/34 (H1N1) subtype. H1HA10-Foldon, a trimeric derivative of our parent construct (H1HA10), bound conformation-sensitive, stem-directed bnAbs such as CR6261 (30), F10 (31), and FI6v3 (32) with a high-affinity [equilibrium dissociation constant (K_D) of 10–50 nM]. The designed immunogens elicited broadly cross-reactive antiviral antibodies which neutralized highly drifted influenza virus strains belonging to both group 1 (H1 and H5 subtypes) and 2 (H3 subtype) in vitro. Significantly, stem immunogens designed from unmatched, highly drifted influenza strains conferred protection against a lethal (2LD₉₀) heterologous A/Puerto Rico/8/34 virus challenge in mice. Our immunogens confer robust subtype-specific and modest heterosubtypic protection in vivo. In contrast to previous stem domain immunogens (23–25), the designed immunogens were purified from the soluble fraction in E. coli. The HA stem-fragment immunogens do not aggregate even at high concentrations and are cysteine-free, which eliminates the complications arising from incorrect disulfide-linked, misfolded conformations. The aforementioned properties of the HA stem-fragment immunogens make it amenable for scalability at short notice which is vital during pandemic outbreaks.     

Emergency Contraceptive Knowledge and Use among Urban Women in Nigeria and Kenya

Rates of emergency contraceptive (EC) use in sub‐Saharan Africa are highest in Kenya and Nigeria, although little is known about user characteristics and use dynamics in these countries. To better meet women's emergency contraceptive needs and to contribute to the limited knowledge base regarding this method in Africa, this study examines data from a sample of EC users drawn from a large, representative household survey that included sexually experienced women in urban Kenya and Nigeria. Bivariate and multivariate analyses reveal greater knowledge of EC among these urban women than was reported in other nationally representative surveys. Recent users of EC were more likely to be in their 20s, unmarried, and more highly educated than never users or ever users of EC in both countries. Results contradict public perceptions of EC users as young adolescents and indicate the importance of strengthening EC provision in Africa, including targeting information and services to unmarried women and supporting private pharmacies in delivering quality services.     

Rolling Circle Amplification for Direct Detection of rpoB Gene Mutations in Mycobacterium tuberculosis Isolates from Clinical Specimens

Rapid and accurate detection of multidrug resistance (MDR) in Mycobacterium tuberculosis is essential to improve treatment outcomes and reduce global transmission but remains a challenge. Rifampin (RIF) resistance is a reliable marker of MDR tuberculosis (TB) since by far the majority of RIF-resistant strains are also isoniazid (INH) resistant. We have developed a rapid, sensitive, and specific method for detecting the most common mutations associated with RIF resistance, in the RIF resistance determining region (RRDR) of rpoB, using a cocktail of six padlock probes and rolling circle amplification (RCA). We used this method to test 46 stored M. tuberculosis clinical isolates with known RIF susceptibility profiles (18 RIF resistant, 28 susceptible), a standard susceptible strain (H37Rv, ATCC 27294) and 78 M. tuberculosis culture-positive clinical (sputum) samples, 59 of which grew RIF-resistant strains. All stored clinical isolates were correctly categorized, by the padlock probe/RCA method, as RIF susceptible or resistant; the sensitivity and specificity of the method, for direct detection of phenotypically RIF-resistant M. tuberculosis in clinical specimens, were 96.6 and 89.5%, respectively. This method is rapid, simple, and inexpensive and has the potential for high-throughput routine screening of clinical specimens for MDR M. tuberculosis, particularly in high prevalence settings with limited resources.     

Appendicitis as the presenting manifestation of Kawasaki disease

In cases of Kawasaki’s disease (KD) presenting as acute surgical abdomen, rarely has the presence of acute appendicitis been found. We report two cases of histologically confirmed acute appendicitis in the presence of KD and a review of the literature as it pertains to acute abdomen and atypical presentations of KD.     

Percentile rank conversion tables for WAIS-R IQS at six educational levels

Estimated percentile ranks for Verbal, Performance, and Full Scale IQs are provided for the WAIS-R at six educational levels (N = 1,880). These tables are based on means and standard deviations from the standardization sample. Application of the tables is discussed, as are implications for clinical practice.