The effect of estradiol valerate and allylestrenol on endometrial transformation in hypergonadotropic hypogonadic women

The effect of estradiol valerate and allylestrenol on the endometrial transformation of five hypergonadotropic hypogonadic women was evaluated. Estradiol valerate was administered throughout the whole induced cycle (28 days), while allylestrenol was added during the second half of the cycle. Endometrial biopsies were performed during allylestrenol treatment and were evaluated histologically. Samples of endometrium were also subjected to one-dimensional SDS electrophoresis. Of ten biopsies performed, only one was interpreted to be in-phase, while the others were dated proliferative (4 biopsies) or showed abortive or out-of-phase secretory transformation. The highest mean serum progesterone level, detected under allylestrenol treatment, was 1.5 ng/ml. Protein electrophoresis demonstrated relative sequential changes in the protein patterns of the 115 kDa and 150 kDa protein bands. It is concluded that allylestrenol, although having gestagen properties, may not be efficient for the induction of an adequate secretory transformation of human endometrium in the absence of ovaries.     

Polymorphism of germ-line immunoglobulin VH genes correlates with allotype and idiotype markers

The polymorphic nature of the immunoglobulin V_H genes was investigated by Southern blot analysis of liver DNA of sixteen different mouse strains and hybridization with V_H probes. Differences in restriction enzyme pattern (REP) were observed and six different patterns of restriction fragments were found for the sixteen strains analyzed. No equivalent polymorphism was observed in another multigene family, the actins. The six patterns correlate with immunoglobin constant region allotypes (Igh-1). Experiments with Igh-1-congenic strains suggest that the V_H REP is linked to immunoglobulin constant region haplotype. Mouse strains which share inherited idiotypes also share identical V_H restriction pattern. This provides a structural basis for the genetic linkage between idiotypes and allotypes. It also indicates that different strains carry different VH gene repertoires, which may be the basis for the expression of different inherited idiotypes in various strains. We propose that a V_H group is a set of linked genes that are coinherited as a cluster with the constant region genes and that V_H and C_H can be regarded as an extended haplotype.     

Fryns syndrome: a predictable, lethal pattern of multiple congenital anomalies

Fryns syndrome is a unique pattern of lethal multiple congenital malformations with variable expression. A family in which all four sibs conformed to Fryns syndrome is detailed and substantiates the criteria for definition of the syndrome; perinatal mortality, hypoplastic lungs, and facial deformities should be highly suggestive of the syndrome. The addition of a strong family history, diaphragmatic hernias, distal limb deformities, and early onset of polyhydramnios with subsequent premature delivery should definitely confirm the diagnosis.     

Antigen-induced conformational changes in antibodies and their Fab fragments studied by circular polarization of fluorescence.

Conformational changes induced in antibody molecules and in their Fab fragments by binding of antigen were investigated by the circular polarization of the fluorescence emitted by the tryptophan residues. This property of the fluorescence is related to the asymmetry, and thus to the conformation and environment, of the emitting chromophore. Changes in the circular polarization of the fluorescence of the antibody were observed upon binding of RNase to anti-RNase, of poly(DL-alanyl)-poly(L-lysine) to antipoly(D-alanine), and of the "loop" of lysozyme, a monovalent antigenic determinant, to anti"loop." The spectral changes were observed at different antigen-antibody ratios, including high antigen excess, indicating that they are due to antigen binding and not to aggregation. The circular polarization of fluorescence also detects changes in conformation of the different Fab fragments upon binding of the corresponding antigens. These changes in conformation were, however, markedly different from those observed for the whole antibody molecules, and indicated an interaction between the Fc and Fab fragments in the antibody molecule, and probably a change in the conformation of Fc upon binding of antigen to the antibody. In contrast, the small hapten, phosphorylcholine, did not induce a change in the circular polarization of the fluorescence of its antibody or corresponding Fab fragments. Reduction of the interchain disulfide bonds of the antibodies abolished the antigen-induced spectral changes due to the presence of the Fc portion in the molecule, but not the changes observed in Fab, suggesting that the disulfide bonds at the hinge region of the antibody are required for the transmission of the conformational change from the Fab to the Fc.     

Modulation of c-kit expression in pancreatic adenocarcinoma: A novel stem cell marker responsible for the progression of the disease

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of late symptoms and resistance to chemotherapy and radiation therapy. We have investigated the appearance of c-kit, a stem cell marker, in both normal adult pancreatic tissue and in cancerous tissue. Apart from some very pale staining of islets of Langerhans, normal pancreas was devoid of staining with antibodies to c-kit. In contrast, in cancerous tissue that still preserves the overall integrity of the pancreatic tissue, there was a clear labeling in islets of Langerhans, which seemed to be co-localized with insulin containing β cells. In other cases, where the pancreatic tissue was completely deteriorated, intensive labeling was clearly evident in remnants of both the exocrine and the endocrine tissues. The duct cells of the adenocarcinoma were moderately but clearly labeled with antibodies to c-kit. In contrast, in metastasis of PDAC, very intensive labeling of c-kit was evident. The location of KRAS, which is strongly associated with PDAC, was also analyzed at the initial stages of the disease, when islets of Langerhans still preserve their integrity to a large extent. KRAS was found exclusively in islets of Langerhans and overlapped in its location with insulin and c-kit expressing cells. It is suggested that the modulation of the expression of c-kit, visualized by antibodies to the oncogene molecule, may play an important role in the formation and progression of PDAC. The absence of c-kit in normal pancreas and its appearance in PDAC is probably due to a mutational event, which probably allows conversion of the β cells into cancer stem cells (CSC). Co-expression of both c-kit and KRAS, typical markers for CSC with overlapping with insulin in islets of Langerhans, strongly support the notion that β-cells play a central role in the development of PDAC. The use of specific drugs that can attenuate the kinase activity of c-kit or target KRAS expressing cancer cells should be tested in order to attenuate the progression of this lethal disease.     

Inferior Alveolar Neurosensory Deficiency Associated With Placement of Dental Implants

Background: This study reports and analyzes a large series of patients with neurosensory deficiency related to the placement of dental implants (DIs) and resulting in liability claims (LCs). Methods: From 1998 to 2009, there were 92 LCs related to persistent altered sensation post DI placements in Israel. Patients’ demographics, year and source of LCs, interval between the procedure that resulted in a neurosensory deficiency and the LC, qualifications of the surgeon, preoperative imaging modality, DI length, available alveolar bone for DI placement, placement site, timing of DI placement (immediately after tooth extraction or after socket healing), and treatment after the diagnosis of neurosensory deficiency were recorded and analyzed. Results: There were 21 cases during the first 5 years of the study (mean 4.2/year) and 63 cases (mean 12.6/year) over the following 5 years. Thirty LCs were issued during the second postoperative year and 15 LCs after >5 years. Most LCs (76%) involved procedures that were planned and performed according to radiographs and 24% after computed tomography. Sixty‐five percent of the LCs were performed by general dental practitioners and 35% by specialists. More than one DI was performed during the surgical procedure that resulted in a neurosensory deficiency in 73 LCs (79.3%), and the DI was >10 mm in 55 (59.8%) cases. Conclusions: LCs for DIs that result in a neurosensory deficiency pose a legal risk to the practitioner long after the injury has occurred.     

Cloning and expression of a widely expressed receptor tyrosine phosphatase.

We describe the identification of a widely expressed receptor-type (transmembrane) protein tyrosine phosphatase (PTPase; EC 3.1.3.48). Screening of a mouse brain cDNA library under low-stringency conditions with a probe encompassing the intracellular (phosphatase) domain of the CD45 lymphocyte antigen yielded cDNA clones coding for a 794-amino acid transmembrane protein [hereafter referred to as receptor protein tyrosine phosphatase alpha (R-PTP-alpha)] with an intracellular domain displaying clear homology to the catalytic domains of CD45 and LAR (45% and 53%, respectively). The 142-amino acid extracellular domain (including signal peptide) of R-PTP-alpha is marked by a high serine/threonine content (32%) as well as eight potential N-glycosylation sites but displays no similarity to known proteins. Genetic mapping assigns the gene for R-PTP-alpha to mouse chromosome 2, closely linked to the Il-1a and Bmp-2a loci. The corresponding mRNA (3.0 kilobases) is expressed in most murine tissues and most abundantly expressed in brain and kidney. Antibodies against a synthetic peptide of R-PTP-alpha identified a 130-kDa protein in cells transfected with the R-PTP-alpha cDNA.     

Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.

OBJECTIVE: To overview the world literature on ovarian hyperstimulation syndrome (OHSS) and modes of prevention and treatment of OHSS. STUDY SELECTION: All the pertinent literature on OHSS, its prevention, and strategies for treatment were reviewed. PREVENTION: Key to prevention is proper identification of the population at risk, which includes women with either the hormonal or the morphological signs of polycystic ovarian disease, high serum estradiol (E2) before human chorionic gonadotropin (hCG) administration (E2 greater than 4,000 pg/mL), multiple follicular response (greater than 35), younger age, and lean habitus. When a high risk situation is recognized, ovulatory dose of hCG may be reduced, avoided (with cycle cancellation), or substituted by gonadotropin-releasing hormone or its agonist. Luteal support with hCG is to be bypassed. To minimize risk of OHSS, endogenous pregnancy-drived hCG may be eluded by judicious cryopreservation of all embryos. Last, follicular aspiration will allow higher levels of E2 and larger number of follicles to be matured with lesser risk of OHSS than conventional ovulation induction without follicular aspiration. TREATMENT: In-house for the severe and intensive care for the critical form. Meticulous fluid and electrolyte balance using both crystalloids and colloids (albumin) until hemoconcentration abates. Paracentesis is indicated for tight ascites, deteriorating kidney functions, and symptomatic relief. Diuretics may be prudently used once hemodilution is achieved. Dopamine drip may be used as a renal rescue, whereas heparin is indicated for thromboembolic phenomena and surgery reserved for abdominal catastrophies. Therapeutic interruption of an early gestation may be lifesaving when all other measures have failed. CONCLUSIONS: Although severe and critical OHSS may not be completely avoided, early recognition of high-risk factors, judicious prevention schemes, and treatment strategies should reduce the complication and long-term sequelae of this iatrogenic syndrome.     

Clinical evaluation of three approaches to micromanipulation-assisted fertilization

Three different micromanipulation procedures were used to assist human fertilization in cases of severe male factor infertility. Zona drilling was performed either with acid Tyrode's solution, mechanically following zona softening with chymotrypsin, or by partial zona dissection. The fertilization rate was lowest in the zona drilling/acid Tyrode's group (7/40; 17.5%), although no differences between groups (zona drilling/chymotrypsin: 21/84, 25%; partial zona dissection: 31/143, 21.7%) were significant. The fertilization rate was significantly increased relative to untreated eggs from the same patients only in the partial zona dissection group (31/143, 21.7% versus 4/102, 3.9%). Oocyte damage occurred at a high rate as a result of zona drilling with acid Tyrode's solution (13/41, 37%). Embryonic development was compromised after zona drilling with chymotrypsin: only 7/12 (58.3%) of the fertilized oocytes cleaved, and the morphology of many of the cleaved embryos was abnormal. Although only 61% (16/26) of the diploid embryos resulting from partial zona dissection cleaved, the embryonic morphology of these embryos was comparable with controls. No pregnancies resulted from the transfer of manipulated embryos. We conclude that although zona manipulation increases the fertilization rate, losses due to oocyte trauma, low rates of diploid fertilization, low rates of cleavage, and a high frequency of abnormal cleavage reduce the number of embryos available for transfer.