Homozygous CRYBB1 deletion mutation underlies autosomal recessive congenital cataract

PURPOSE: Some 30% of cases of congenital cataract are genetic in origin, usually transmitted as an autosomal dominant trait. The molecular defects underlying some of these autosomal dominant cases have been identified and were demonstrated to be mostly mutations in crystallin genes. The autosomal recessive form of the disease is less frequent. To date, only four genes and three loci have been associated with autosomal recessive congenital cataract. Two extended unrelated consanguineous inbred Bedouin families from southern Israel presenting with autosomal recessive congenital nuclear cataract were studied. METHODS: Assuming a founder effect, homozygosity testing was performed using polymorphic microsatellite markers adjacent to each of 32 candidate genes. RESULTS: A locus on chromosome 22 surrounding marker D22S1167 demonstrated homozygosity only in affected individuals (lod score > 6.57 at theta = 0 for D22S1167). Two crystallin genes (CRYBB1 and CRYBA4) located within 0.1 cM on each side of this marker were sequenced. No mutations were found in CRYBA4. However, an identical homozygous delG168 mutation in exon 2 of CRYBB1 was discovered in affected individuals of both families, generating a frameshift leading to a missense protein sequence at amino acid 57 and truncation at amino acid 107 of the 252-amino-acid CRYBB1 protein. Denaturing [d]HPLC analysis of 100 Bedouin individuals unrelated to the affected families demonstrated no CRYBB1 mutations. CONCLUSIONS: CRYBB1 mutations have been shown to underlie autosomal dominant congenital cataract. The current study showed that a different mutation in the same gene causes an autosomal recessive form of the disease.     

Targeted Gene-and-host Progenitor Cell Therapy for Nonunion Bone Fracture Repair

Nonunion fractures present a challenge to orthopedics with no optimal solution. In-vivo DNA electroporation is a gene-delivery technique that can potentially accelerate regenerative processes. We hypothesized that in vivo electroporation of an osteogenic gene in a nonunion radius bone defect site would induce fracture repair. Nonunion fracture was created in the radii of C3H/HeN mice, into which a collagen sponge was placed. To allow for recruitment of host progenitor cells (HPCs) into the implanted sponge, the mice were housed for 10 days before electroporation. Mice were electroporated with either bone morphogenetic protein 9 (BMP-9) plasmid, Luciferase plasmid or injected with BMP-9 plasmid but not electroporated. In vivo bioluminescent imaging indicated that gene expression was localized to the defect site. Microcomputed tomography (µCT) and histological analysis of murine radii electroporated with BMP-9 demonstrated bone formation bridging the bone gap, whereas in the control groups the defect remained unbridged. Population of the implanted collagen sponge by HPCs transfected with the injected plasmid following electroporation was noted. Our data indicate that regeneration of nonunion bone defect can be attained by performing in vivo electroporation with an osteogenic gene combined with recruitment of HPCs. This gene therapy approach may pave the way for regeneration of other skeletal tissues.     

Plasma from the second and third weeks after open colorectal resection for cancer stimulates in vitro endothelial cell growth,migration, and invasion

Introduction  

Angiogenesis is central to wound healing and tumor growth. Postoperative (postop) plasma from weeks 2 and 3 after minimally invasive colorectal resection (MICR) stimulates endothelial cell (EC) migration (MIG), invasion (INV), and proliferation (all vital to angiogenesis) compared with preoperative (preop) plasma results and may promote postop tumor growth. The purpose of this study was to determine whether plasma from open colorectal resection (OCR) patients has similar proangiogenic EC effects in vitro.     

Aneurysm Clips: Twenty Years Later

Abstract

The ability of the central nervous system (CNS) to store and release fluid energy plays an important role in both health and disease. The stored fluid energy is the product of the fluid volume and pressure. How changes in CNS fluid (CSF, blood, or extracellular fluid) energy are distributed is determined by the compliance of the fluid containers and their arrangement. Hydrocephalus and related diseases not only interfere with the absorption of CSF but also interfere with the exchange of CSF in response to positional changes, cardiorespiratory and intraperitoneal energy changes. While shunts allow for the diversion of CSF when the intracranial energy exceeds the absorbing receptacle energy, they do not normalize the return of CSF to the intracranial compartment as needed with the intracranial blood volume or pressure decreases (the accumulator function of the CNS’s CSF). A CSF shunt that has an artificial accumulator proximal to the valve can potentially restore the accumulator function towards normal and prevent some of the complications associated with CSF overdrainage. [Neural Res 2000; 22: 4-18]     

Laparoscopic adrenalectomy for malignant lesions: surgical principles to improve oncologic outcomes

Background

Laparoscopic adrenalectomy (LA) is the treatment of choice for benign adrenal lesions. Size of the lesion and radiologic features define the risk for malignancy. In lesions at high risk of malignancy, the experience with the laparoscopic approach is limited and therefore controversial. The purpose of this study was to determine the feasibility and oncological safety of LA for malignant disease.

Methods

Retrospective analysis of prospectively collected database. All LA performed in our department from 2003 to 2011 were reviewed and demographic, perioperative, and follow-up data for those who had malignancy in the final histological report was analyzed. Data are presented as mean ± standard deviation or median (range).

Results

Of 121 LA, we identified 20 patients with 21 malignant adrenal pathologies: 11 primary tumors, 5 adrenocortical carcinoma, 5 large B cell lymphoma, and 1 leiomyosarcoma. Ten metastatic lesions included 5 malignant melanoma (1 patient, both sides), 4 adenocarcinoma, and 1 renal cell carcinoma. There was no conversion to laparotomy. Tumor size was 4.5 (1–9.5) cm, operative duration was 79 (42–262) min, and estimated blood loss was 40 (0–250) ml. All patients resumed regular diet on postoperative day 1, and the median length of stay was 2 days after surgery. Two patients died at 6 and 24 months postoperatively. Three patients were lost to follow-up. All the rest of the patients were disease-free at a follow-up of 58 (7–96) months.

Conclusions

LA for primary or metastatic malignant lesions is feasible and seems oncologically safe. Surgical principles should be the same for all LA: en bloc resection of all epinephric fat, minimal touch technique, and low threshold for conversion. Size of the lesion alone should not be an indication for open surgery.     

miR-155 regulates HGAL expression and increases lymphoma cell motility

HGAL, a prognostic biomarker in patients with diffuse large B-cell lymphoma and classic Hodgkin lymphoma, inhibits lymphocyte and lymphoma cell motility by activating the RhoA signaling cascade and interacting with actin and myosin proteins. Although HGAL expression is limited to germinal center (GC) lymphocytes and GC-derived lymphomas, little is known about its regulation. miR-155 is implicated in control of GC reaction and lymphomagenesis. We demonstrate that miR-155 directly down-regulates HGAL expression by binding to its 3'-untranslated region, leading to decreased RhoA activation and increased spontaneous and chemoattractant-induced lymphoma cell motility. The effects of miR-155 on RhoA activation and cell motility can be rescued by transfection of HGAL lacking the miR-155 binding site. This inhibitory effect of miR-155 suggests that it may have a key role in the loss of HGAL expression on differentiation of human GC B cells to plasma cell. Furthermore, this effect may contribute to lymphoma cell dissemination and aggressiveness, characteristic of activated B cell-like diffuse large B-cell lymphoma typically expressing high levels of miR-155 and lacking HGAL expression.     

Failure of selective termination and dexamethasone rescue therapy to arrest HELLP syndrome in a midtrimester triplet gestation with one triploid fetus.

We present a case of a patient with a triplet pregnancy at 22 weeks with one triploid fetus (69XXX) who developed severe preeclampsia that did not reverse with dexamethasone rescue therapy and selective termination. With multiple gestations on the rise and the early diagnosis of abnormal pregnancies being accomplished through ultrasound, serum markers, and invasive procedures, the question remains if there is a point in gestation before which selective termination of an abnormal fetus would allow the pregnancy to continue without preeclampsia developing or progressing. Appropriate counseling as to the maternal risk in cases of trisomy 13 or triploidy is essential as early in pregnancy as possible.     

Distribution of immunoreactive dynorphin A1–8 in discrete nuclei of the rat brain: Comparison with dynorphin A

The distribution of immunoreactive (ir)-dynorphin A1-8 (Dyn A1-8) in 78 microdissected rat brain areas as well as in the neurointermediate lobe of pituitary gland was determined using a highly specific radioimmunoassay. The highest concentrations of Dyn A1-8 in brain were found in substantia nigra (673.8 fmol/mg protein) and lateral preoptic area (565.1 fmol/mg protein). High concentrations of ir-Dyn A1-8 (greater than 240 fmol/mg protein) were found in 5 nuclei: ventral premamillary nucleus, anterior hypothalamic nucleus, dorsomedial nucleus, arcuate nucleus, and medullary reticular nuclei. Moderate concentrations of the peptide (between 120 and 240 fmol/mg protein) were found in 55 brain nuclei such as septal and amygdaloid nuclei, most diencephalic structures, mesencephalic nuclei, pons and medulla oblongata nuclei and others. Low concentrations of ir-Dyn A1-8 (less than 120 fmol/mg protein) were found in 16 regions, e.g. frontal cortex, hippocampus, caudate-putamen cortical amygdaloid nucleus, several thalamic nuclei, mamillary body superior and inferior colliculi, cerebellar nuclei and others. The posterior thalamic nucleus has the lowest ir-Dyn A1-8 concentration (62.0 fmol/mg protein). The neurointermediate lobe of the pituitary gland is extremely rich in ir-Dyn A1-8 (4063.0 fmol/mg protein).