Aortic valve insufficiency (AI) at the time of left ventricular assist device (LVAD) insertion needs to be corrected, however there is little known about how to manage bioprosthetic valvular AI.
A 55-year-old female with dilated cardiomyopathy who previously had a bioprosthetic aortic valve replacement needed a LVAD as a bridge to transplant. Her left ventricular ejection fraction was 10% and had mild to moderate transvalvular AI. She underwent a HeartWare HVAD insertion along with aortic valvular coaptation stitch repair (Park's stitch) to the bioprosthetic valve.
Her AI improved to trivial with minimal ejection through the bioprosthetic valve. She was transplanted 6 months following the surgery. A Park's stitch to the bioprosthetic aortic valve with more than mild AI might be a good option for bridge to transplant patient.
Aortic insufficiency; Aortic valve repair; Park’s stitch; Bioprosthetic valve; Left ventricular assist device
Inhibitory interneurons in the neocortex often connect in a promiscuous and extensive fashion, extending a “blanket of inhibition” on the circuit. This raises the problem of how can excitatory activity propagate in the midst of this widespread inhibition. One solution to this problem could be the vasoactive intestinal peptide (VIP) interneurons, which disinhibit other interneurons. To explore how VIP interneurons affect the local circuits, we use two-photon optogenetics to activate them individually in mouse visual cortex in vivo while measuring their output with two-photon calcium imaging. We find that VIP interneurons have narrow axons and inhibit nearby somatostatin interneurons, which themselves inhibit pyramidal cells. Moreover, via this lateral disinhibition, VIP cells in vivo make local and transient “holes” in the inhibitory blanket extended by SOM cells. VIP interneurons, themselves regulated by neuromodulators, may therefore enable selective patterns of activity to propagate through the cortex, by generating a “spotlight of attention”.
SIGNIFICANCE STATEMENT Most inhibitory interneurons have axons restricted to a nearby area and target excitatory neighbors indiscriminately, raising the issue of how neuronal activity can propagate through cortical circuits. Vasoactive intestinal peptide-expressing interneurons (VIPs) disinhibit cortical pyramidal cells through inhibition of other inhibitory interneurons, and they have very focused, “narrow” axons. By optogenetically activating single VIPs in live mice while recording the activity of nearby neurons, we find that VIPs break open a hole in blanket inhibition with an effective range of ∼120 μm in lateral cortical space where excitatory activity can propagate.
disinhibition; interneuron; neocortex; vasoactive intestinal peptide; VIP
Supplemental Digital Content is available in the text.
We present a case of a 65-year-old man with cutaneous T-cell lymphoma treated with radiation therapy and an allogeneic hematopoietic stem cell transplant from his human leukocyte antigen-matched brother. Engraftment was successful, but the patient went on to develop painful, radiation-induced ulcers. The ulcers were fat-allografted using liposuctioned fat from his brother because of the patient’s unique chimeric state. Postprocedure follow-up revealed epithelialization of the ulcer sites and significant improvement in neuropathic pain. Our unique case study supports the use of fat grafting for its restorative purposes and for its ability to alleviate chronic neuropathic pain. Additionally, it appears that our case provides a basis of a general approach to the treatment of radiation-induced ulcers in chimeric patients with lymphoid malignancies.
Right ventricular failure is a serious complication after left ventricular assist device placement.
A 70-year-old male in decompensated heart failure with right ventricular failure after the placement of a left ventricular assist device. A single dual-lumen PROTEKDuo cannula was inserted percutaneously via the internal jugular vein to draw blood from the right atrium and return into the pulmonary artery using the CentriMag system, by passing the failing ventricle. The patient was successfully weaned from right ventricular assist device.
In comparison to two-cannula conventional procedures, this right ventrivular assist device system improves patient rehabilitation and minimizes blood loss and risk of infection, while shortening procedure time and improving clinical outcomes in right ventricular failure.
Circulatory support; Heart failure; Minimally invasive surgery; Right ventricular assist device; PROTEKDuo
With recent advances in imaging modalities and radiation therapy, stereotactic body radiotherapy (SBRT) has allowed for the delivery of high doses of radiation with accuracy and precision. As such, SBRT has generated favorable results in the treatment of several cancers. Although the role of radiation has been controversial for the treatment of pancreatic ductal adenocarcinoma (PDAC) due to rather lackluster results in clinical trials, SBRT may offer improved outcomes, enhance the quality of life, and aid in palliative care settings for PDAC patients. This review delineates the role of SBRT in the treatment of PDAC, presents the defining principles of radiation biology and the radiation oncology work flow, and discusses the prospects of new treatment regimens involving tumor immunology and radiation therapy.
Pancreatic ductal adenocarcinoma (PDAC); stereotactic body radiotherapy (SBRT); radiotherapy; radiation oncology
We recently completed a phase 1 clinical trial demonstrating the safety of a mammaglobin-A DNA vaccine in patients with metastatic breast cancer. We are currently enrolling patients with early stage breast cancer in a phase 1b clinical trial. The mammaglobin-A DNA vaccine will be administered concurrently with neoadjuvant endocrine therapy, providing a unique opportunity to examine the impact of vaccination in the tumor microenvironment.
Cancer vaccine; breast cancer; immunotherapy; mammaglobin-A; DNA vaccine; T cells
Effective treatment of bacterial infection relies on timely diagnosis and proper prescription of antibiotic drugs. The antimicrobial susceptibility test (AST) is one of the most crucial experimental procedures, providing the baseline information for choosing effective antibiotic agents and their dosages. Conventional methods, however, require long incubation times or significant instrumentation costs to obtain test results. We propose a lab-on-a-chip approach to perform AST in a simple, economic, and rapid manner. Our assay platform miniaturizes the standard broth microdilution method on a microfluidic device (20 × 20 mm) that generates an antibiotic concentration gradient and delivers antibiotic-containing culture media to eight 30-nL chambers for cell culture. When tested with 20 μL samples of a model bacterial strain (E. coli ATCC 25922) treated with ampicillin or streptomycin, our method allows for the determination of minimum inhibitory concentrations consistent with the microdilution test in three hours, which is almost a factor of ten more rapid than the standard method.
antibiotics; AST; microfluidics; microdevice; lab-on-a-chip; MIC
To test the effects of varying vitrification protocols on the cell cycle status and chromosomal integrity in cumulus-enclosed GV stage rat oocytes.
Vitrified and thawed rat oocytes were labeled with fluorescent markers for chromatin, cell cycle activation, and f-actin and analyzed by conventional and laser scanning confocal microscopy.
In all vitrification groups, significant alterations in cumulus cell connectivity, cell cycle status, and cytoplasmic actin integrity were observed following warming compared to fresh control oocytes. Based on the protein phosphorylation marker MPM-2, it is clear that warmed oocytes rapidly enter M-phase but are unable to maintain chromosome integrity as a result of multiple chromatin fusions. A prominent reduction in f-actin is evident in both the ooplasm and at the cortex of vitrified oocytes. Finally, an irreversible but irregular retraction of TZPs occurs on the majority of oocytes subjected to any of the vitrification protocols.
These findings draw attention to undesirable consequences of immature oocyte vitrification that compromise cell cycle status and chromatin and cytoskeleton integrity that may not be evident until after fertilization.
Vitrification; Oocyte cryopreservation; Fertility preservation; F-actin; Immature oocytes; Chromatin patterns; GV stage oocytes; MPM-2; Confocal microscopy
Patient: Female, 16
Final Diagnosis: Castleman’s Disease
Symptoms: Chest pain • cough non-productive
Clinical Procedure: —
Castleman’s disease, or angiofollicular lymphoid hyperplasia, is a rare disorder and can be easily misdiagnosed as lymphoma, neoplasm, or infection. The diagnosis is challenging due to the nonspecific signs and symptoms as well as the rarity of the disease. We present an unusual case of a young girl presenting with an enlarging pulmonary mass that was believed to be infectious in origin.
A 16-year-old Native American female from Arizona initially presented with occasional non-productive cough and chest pain. Imaging revealed a 3-cm left upper lobe lobulated mass. This mass was thought to be due to coccidioidomycosis and was treated with fluconazole. Follow-up imaging demonstrated growth of the mass to 4.8 cm. The patient underwent a left video-assisted thoracoscopic left upper lobectomy and mediastinal lymphadenectomy. Histopathological examination revealed Castleman’s disease.
Pulmonary masses in young patients can be easily misdiagnosed as infections or cancer. We present the case of a 16-year-old female misdiagnosed as having a fungal infection of the lung, which was later revealed to be Castleman’s disease of the left upper lobe.
Coccidioidomycosis; Giant Lymph Node Hyperplasia
•This case report highlights a rare type of esophageal polyps (inflammatory fibroid polyp).•This case report presents a giant esophageal inflammatory fibroid polyp.•This case report represents the second reported case for giant inflammatory fibroid polyps that is originated from the upper esophagus.
Benign inflammatory fibroid polyps (IFP) are rare submucosal tumors of the upper gastrointestinal tract. Rarely, they can develop in the esophagus, usually in the lower third. There are only 12 cases of giant IFP of the esophagus reported in literature and little is known about their origin, biological behavior and operative management. We present a patient with a giant benign IFP of the esophagus that originated from the upper esophagus.
The patient is a 59-year-old male who presented with dysphagia. Upper endoscopy and esophagram revealed a giant intraluminal esophageal mass with a pedicle in the upper esophagus. Resection of this mass was performed through a left cervical esophagotomy. Pathology confirmed IFP, On 2 year follow up, there was no recurrence of the mass.
A giant IFP is defined as an IFP greater than 4 cm, commonly present in the distal esophagus. Pathology usually reveals vascularized fibrous stroma with elements of inflammatory infiltrate. This mass is slow-growing and asymptomatic until it grows to a large size. Common diagnostic studies include barium esophagram, upper endoscopy, and CT imaging. A key pre-operative work-up is to identify the location of the pedicle to plan out surgical approach and to avoid injuring the rich blood supply thus preventing a life threatening hemorrhage during the operation.
Giant IFPs are infrequent in clinical practice. Resection is indicated and usually performed by a surgical intervention or endoscopic removal. The pathogenesis of these polyps remains poorly understood due to the rarity of these lesions.
Esophagus; Surgery; Inflammatory fibroid polyps; Giant polyps
To review the benefits of adjuvant systemic therapy given to women with breast cancer of reproductive age, its effects on fertility, and options for fertility preservation.
Publications relevant to fertility preservation and breast cancer were identified through a PubMed database search.
Most women who develop invasive breast cancer under age 40 will be advised to undergo adjuvant chemotherapy with or without extended antihormonal therapy to reduce the risk of recurrence and death from breast cancer. Adjuvant chemotherapy particularly with alkylating agents such as cyclophosphamide is gonadotoxic and markedly accelerates the rate of age-related ovarian follicle loss. Although loss of fertility is an important issue for young cancer survivors, there is often little discussion about fertility preservation before initiation of adjuvant therapy. Greater familiarity with prognosis and effects of different types of adjuvant therapy on the part of infertility specialists and fertility preservation options such cryopreservation of embryos, oocytes, and ovarian tissue on the part of oncologists would facilitate these discussions. Establishment of rapid fertility consultation links within cancer survivorship programs can help ensure that every young woman who is likely to undergo gonadotoxic cancer treatment is counseled about the effects of therapy and options available to her to increase the likelihood of childbearing after cancer treatment.
Breast cancer; fertility preservation; embryo cryopreservation; oocyte cryopreservation; ovarian tissue cryopreservation; ovarian transplantation; GnRH agonist; chemotherapy; cancer survivorship
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2′-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), along with increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
The need for practice guidelines for fertility preservation in young women with hematological malignancies has been increased. To develop recommendations, publications relevant to fertility preservation and hematological cancers were identified through a PubMed database search and reviewed systematically, focusing on the effects of oncological treatments on fertility as well as on the efficacy, feasibility and risks of existing fertility preservation methods.
Hematological malignancy; Fertility; Fertility preservation; Chemotherapy; Lymphoma; Leukemia, cancer
To assess the longevity of ovarian grafts in five cancer patients who underwent heterotopic autotransplantation of frozen-thawed ovarian tissue.
Five cancer survivors underwent heterotopic ovarian transplantation between 2001and 2011. Stored ovarian tissue (for 1–10 years) was rapidly thawed and transplanted into the space between the rectus sheath and the rectus muscle (8–20 cortical sections per patient). Endocrine function was assessed by monthly blood tests (FSH, LH, E2, progesterone and testosterone) and ultrasound after transplantation. The monitoring was continued until the cessation of endocrine function by consecutive blood tests (E2 < 20 pg/ml; FSH ≥ 35 IU/L).
Endocrine function was restored in all patients between 12–20 weeks after transplantation. Four patients required the second transplantation one to two years after the first transplantation. The duration of endocrine function after the second transplantation was much longer (9 months–84 months). The longest duration of endocrine function was seen in a woman who underwent ovarian transplantation in 2003 and 2004 after radiotherapy for cervical cancer. Even more than seven years after transplantation, endocrine function has not ceased (FSH 9.5, E2 108, on July 1, 2011). Of note, this patient underwent three IVF cycles in 2004 which resulted in four embryos.
Long-term endocrine function lasting for seven years can be established with heterotopic transplantation of cryobanked human ovarian tissue. Re-establishment of long-term endocrine function after ovarian transplantation will benefit young cancer survivors with premature ovarian failure.
Fertility preservation; Ovarian transplantation; Heterotopic transplantation; Endocrine function; Cancer; Cryopreservation; Ovarian tissue
When a young woman is diagnosed with breast cancer, there is often a sense of urgency by the patient and her providers to initiate treatment. This article provides guidelines for incorporating the discussion of fertility preservation with newly diagnosed young women with breast cancer.
Fertility preservation; Breast cancer; Chemotherapy; Cancer; Survivorship; Oocyte cryopreservation; Embryo cryopreservation; Ovarian tissue cryopreservation; Ovarian stimulation; Infertility
Estrous cycle disruption after spinal cord injury (SCI) in female rats is a common phenomenon. It remains unknown, however, if the aberrant estrous cycle is a result of an injury to the spinal cord itself or due to the general stress associated with surgical interventions. We addressed this issue by determining estrous cyclicality in female rats after a spinal cord hemisection (HX), implantation of EMG wires into selected hindlimb muscles, and/or injections of tracer dyes into the spinal cord. Since it is known that aerobic exercise can enhance the recovery of locomotor function in rodents with an incomplete SCI, we also determined if locomotor training positively impacts the disrupted estrous cycle after a HX. Estrous cycle assessments were made during a 5-8 week period in 27 female rats before and after HX, EMG, and/or dye injection surgeries and in HX rats that recovered spontaneously or underwent locomotor training. Our results show that estrous cyclicality was disrupted (cycle length >5 days) in approximately 76%, 46%, and 50% of the rats after HX, EMG, and dye injection surgeries, respectively. The cyclicality, however, was disrupted for a longer period after HX than after EMG or dye injection surgeries. Furthermore, estrous cycle mean length was shorter in the trained than non-trained HX group. These results suggest that estrous cycle disruption after a major SCI is a consequence of both the direct injury to the spinal cord and to the associated stress. Moreover, moderate aerobic exercise initiated early after a spinal cord HX returns the duration of the estrous cycle towards normal.
spinal cord injury; surgical intervention; EMG surgery; estrous cycle; rodents
Background & Aims
Krüppel-like factor 5 (KLF5) is transcription factor that is expressed by dividing epithelial cells of the intestinal epithelium. KLF5 promotes proliferation in vitro and in vivo and is induced by mitogens and various stress stimuli. To study the role of KLF5 in intestinal epithelial homeostasis, we examined the phenotype of mice with conditional deletion of Klf5 in the gut.
Mice were generated with intestinal-specific deletion of Klf5 (Vil-Cre;Klf5fl/fl).
Morphological changes in the small intestine and colon were examined by immunohistochemistry, immunoblotting, and real-time PCR.
Klf5 mutant mice were born at a normal Mendelian ratio but had high mortality compared to controls. Complete deletion of Klf5 from the intestinal mucosa resulted in neonatal lethality that corresponded with an absence of epithelial proliferation. Variegated intestinal-specific deletion of Klf5 in adult mice resulted in morphological changes that included a regenerative phenotype, impaired barrier function, and inflammation. Adult mutant mice exhibited defects in epithelial differentiation and migration. These changes were associated with reduced expression of Cdx 1, Cdx2, and Eph and ephrin signaling proteins. Concomitantly, Wnt signaling to β-catenin was reduced. Proliferation in regenerative crypts was associated with increased expression of the progenitor cell marker Sox9.
Deletion of Klf5 in the gut epithelium of mice demonstrated that KLF5 maintains epithelial proliferation, differentiation, and cell positioning along the crypt radial axis. Morphological changes that occur with deletion of Klf5 are associated with disruption of canonical Wnt signaling and increased expression of Sox9.
intestinal homeostasis; gastrointestinal development; genetics; GI tract
Fertility issues should be addressed to all patients in reproductive age before cancer treatment. In men, cryopreservation of sperm should be offered to all cancer patients in reproductive age regardless of the risk of gonadal failure. In women, the recommendation of fertility preservation should be individualized based on multiple factors such as the urgency of treatment, the age of the patient, the marital status, the regimen and dosage of cancer treatment.
Fertility preservation; Cancer; Lymphoma; Leukemia; Breast cancer; Chemotherapy; Ovarian tissue cryopreservation; Oocyte cryopreservation; Primary ovarian insufficiency; Cancer survival; Gonadal failure; GnRH agonist; Fertility
BACKGROUND & AIMS
Krüppel-like factor 5 (KLF5) is a transcription factor that promotes proliferation; is highly expressed in dividing crypt cells of the gastrointestinal epithelium and is induced by various stress stimuli. We sought to determine the role of KLF5 in colonic inflammation and recovery by studying mice with dextran sulfate sodium (DSS)-induced colitis.
Wild-type (WT) and Klf5+/− mice were given DSS in the drinking water to induce colitis. For recovery experiments, mice were given normal drinking water for 5 days after DSS administration. The extent of colitis was determined using established clinical and histological scoring systems. Immunohistochemical and immunoblotting analyses were used to examine proliferation, migration, and expression of the epidermal growth factor receptor (EGFR).
Klf5 expression was increased in colonic tissues of WT mice given DSS; induction of Klf5 was downstream of mitogen-activated protein kinase signaling. In DSS-induced colitis, Klf5+/− mice exhibited greater sensitivity to DSS than WT mice, with significantly higher clinical and histological colitis scores. In recovery experiments, Klf5+/− mice showed poor recovery, with continued weight loss and higher mortality than WT mice. Klf5+/− mice from the recovery period had reduced epithelial proliferation and cell migration at sites of ulceration compared to WT mice; these reductions correlated with reduced expression of EGFR.
Epithelial repair is an important aspect of recovery from DSS-induced colitis.
The transcription factor KLF5 regulates mucosal healing through its effects on epithelial proliferation and migration.
inflammatory bowel disease; animal model; inflammatory response; mouse