Reversible ventricular dysfunction in cyanotic heart disease.

Ventricular dysfunction is a matter of concern for any preoperative cardiac patient. We describe 2 cases of cyanotic congenital heart disease (CCHD) awaiting on pump repair with hypoxia as a cause of ventricular dysfunction. Any Cyanotic Congenital heart disease presenting with ventricular dysfunction should be evaluated for treatable causes like hypoxia after exclusion of structural causes for the same.

Combined Bentall and modified Ravitch procedures in a patient with Marfan syndrome.

Marfan syndrome is an inherited, connective-tissue disorder transmitted as an autosomal dominant trait. Cardinal features of the disorder include tall stature, ectopia lentis, mitral valve prolapse, aortic root dilatation, and aortic dissection. Pectus excavatum may exist as an isolated lesion or in association with a genetic syndrome such as Marfan syndrome. We report the successful management of a simultaneous correction of pectus excavatum and the underlying cardiovascular diseases.

Lutembacher syndrome with unroofed left superior vena cava: a diagnostic dilemma.

Lutembacher syndrome involving the association of congenital atrial septal defect (ASD), usually of the ostium secundum variety, and mitral valve disease is a well-known entity. Its association with a coronary sinus, ASD, and a persistent left superior vena cava (LSVC) draining into the left atrium (LA) (Raghib syndrome) is rarely described in the literature. This association in a 15-year-old boy erroneously deemed to be inoperable before referral to the authors' hospital due to cyanosis in the presence of atrial septal defect (ASD) and mitral stenosis is described in this report. Evaluation by echocardiography followed by cine angiography confirmed the cause of cyanosis to be drainage of the LSVC into the LA together with an ASD and rheumatic mitral stenosis, a combination of Raghib and Lutembacher syndromes. The boy underwent successful surgical correction. The authors believe this is the second such case to be reported in the English literature and the first of its kind to be managed by surgical intervention.

Elevated levels and fragmented nature of cellular fibronectin in the plasma of gastrointestinal and head and neck cancer patients.

BACKGROUND: Tumor invasion occurs following enzymatic degradation of components of the extracellular matrix. The proteolysis-resistant domains of matrix components are likely to appear in the blood plasma during invasion, and could be used as markers of malignancy. Cellular fibronectin (cFN), a major ECM component, possesses 3 alternately spliced principal protease resistant domains; two of which, extra domain A (EDA) and III connecting segment (IIICS), were selected for this study of the nature of the plasma cFN molecules and its levels in normal subjects (n=51), and patients with gastrointestinal (G-I, n=145) or head and neck (H-N, n=127) cancers. METHODS: ELISA was used to measure the cFN levels in plasma and Western blotting to analyze its fragmented nature in plasma samples from normal individuals and patients with G-I or H-N cancers. RESULTS: cFN in blood plasma, as probed by anti-EDA and anti-IIICS antibodies on Western blots, is found to exist entirely in a fragmented form in normal subjects and G-I and H-N cancer patients. The cFN polypeptides in plasma have Mr of 160 and 100. The levels of plasma cFN, determined by ELISA using the 2 antibodies, are found to be increased in G-I and H-N cancers. In a significant number of stomach (43%), gall bladder (35%) and colon (17%) cancer cases an additional anti-EDA-reactive 30 kD peptide is seen in the plasma. CONCLUSIONS: The mean rise for all sites is statistically significant, and 65% of all patients show cFN levels >80th percentile of normal values. The characterization of the 30 kD peptide showed that it does not contain the IIICS domain and also lacks the central cell- and heparin-binding sites.

Identification of the structural and functional determinants of the extracellular domain of the human follicle stimulating hormone receptor.

The extracellular domain (ECD) of the human follicle-stimulating hormone receptor (hFSHR) is believed to be the major determinant of hormone selectivity. Different discrete, discontinuous regions on the ECD of the hFSHR have been suggested to be crucial for hormone binding. However, the role of the ECD in signal transduction is not well understood. This study provides some insight into these aspects of the structure-function relationship of the ECD of hFSHR. Ten peptides were selected from the ECD on the basis of their ability to be surface oriented, synthesized by the solid-phase method using fluorenylmethyloxycarbonyl chemistry, purified and characterized. They were further studied for their ability to modulate both human follicle-stimulating hormone (hFSH)-FSHR binding and cAMP generation. Competitive inhibition studies showed that, of all the peptides studied, peptides 285-300 and 297-310 hFSHR were able to inhibit hFSH binding to FSHR. Both peptides function as weak competitive inhibitors of hFSH-FSHR binding. Peptides 285-300 hFSHR, 216-235 hFSHR, 184-195 hFSHR, 79-89 hFSHR and 15-31 hFSHR were observed to inhibit FSH-induced cAMP production. In summary, this study suggests that discrete, functional domains of the ECD have a role in hormone binding and signal transduction. Region 285-300 has been identified as a novel region crucial for both FSH binding and cAMP generation.

Attempt to map the receptor binding sites of human follicle-stimulating hormone using disulfide peptides of its beta-subunit indicates major involvement of the regions around disulfide bonds Cys28-Cys82 and Cys32-Cys84 in receptor binding of the hormone.

Follicle-stimulating hormone (FSH) is a heterodimeric glycoprotein hormone secreted by the anterior pituitary. It plays a very important role in folliculogenesis in females and is responsible for spermatogenesis in males. The alpha-subunit which is common within a species and the beta-subunit which is hormone-specific are held together by noncovalent association. This association is very essential for the biological activity of the hormone. Each of these subunits are highly cross-linked by disulfide bonds which appear to stabilize the tertiary structures required for the noncovalent association of the subunits to generate hormonal activity. This study was initiated to delineate the role of the disulfide bonds of hFSH beta in receptor binding of the hormone. Five intermolecular and one intramolecular disulfide peptides corresponding to the disulfide bonds found in hFSH beta were synthesized and screened along with their linear counterparts, for their ability to competitively inhibit the radiolabelled [125I]hFSH from binding to the FSH receptor containing membranes from the testis of immature rats. The disulfide peptides Cys28-Cys82 and Cys32-Cys84 were found to be the most potent in inhibiting radiolabelled hFSH from binding to its receptor. The results suggest the involvement of the regions around disulfide bonds Cys28-Cys82 and Cys32-Cys84 in receptor binding of the hormone. The studies also suggest the involvement of beta L2 and beta L3 loop regions in receptor binding of the hormone. This study is the first of its kind to use disulfide peptides rather than linear peptides to map the receptor binding regions of hFSH.

Effect of active immunization with the C-terminal 67-94 (R-28) region of human seminal plasma inhibin on the fecundity of adult male rabbits.

PROBLEM: To characterize the specificity of antibodies to the synthetic C-terminal 67-94 (R-28) peptide of human seminal plasma inhibin (hSPI), and to examine the effect of active immunization on the fecundity of adult male animals. METHOD OF STUDY: The specificity of R-28-DT antibodies was tested using enzyme-linked immunosorbent assay, immunohistochemical and immunofluorescence staining, and Western blotting. For fertility studies, adult male rats and rabbits were immunized and mated with females of the same strain. RESULTS: Rabbit antibodies to R-28-DT recognized native hSPI, as demonstrated by sperm agglutination in vivo and in vitro, on the sperm head by immunofluorescence staining, and in the columnar epithelial cells of the prostate by immunohistochemical staining. Immunization with the R-28-DT conjugate elicited a poor antibody response in male rats and their fecundity remained unaffected, while in male rabbits it elicited a good immune response with reduction in their fertility. CONCLUSION: R-28-DT antibodies recognized the native hSPI in the prostatic epithelium and agglutinated washed rat, rabbit, monkey, and human spermatozoa in vitro. Immunization of rabbits caused agglutination of spermatozoa resulting in a decrease in their fecundity. The conjugated R-28 peptide of hSPI offers promise as a male contraceptive.

Disulfide bonds Cys(9)-Cys(57), Cys(34)-Cys(88) and Cys(38)-Cys(90) of the beta-subunit of human chorionic gonadotropin are crucial for heterodimer formation with the alpha-subunit: experimental evidence for the conclusions from the crystal structure of hCG.

Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone essential for the establishment and maintenance of pregnancy. The alpha- and beta-subunits of hCG are highly cross-linked internally by disulfide bonds that seem to stabilize the tertiary structures required for the noncovalent association of the subunits to generate hormonal activity. This paper describes the results of our studies on the role of the disulfide bonds of hCG-beta in heterodimer formation with the alpha-subunit. Six disulfide peptides incorporating each of the six disulfide bonds of hCG-beta were screened, along with their linear counterparts, for their ability to competitively inhibit the recombination of alpha- and beta-subunits. The disulfide peptides Cys (9-57), Cys (34-88) and Cys (38-90) were found to inhibit the alpha/beta recombination whereas the remaining three disulfide peptides viz. Cys (23-72), Cys (26-110) and Cys (93-100) did not exhibit any inhibition activity. Interestingly, none of the linear peptides could inhibit the alpha/beta recombination. Results clearly demonstrate that the disulfide bonds Cys(9)-Cys(57), Cys(34)-Cys(88) and Cys(38)-Cys(90) of the beta-subunit of hCG are crucial for heterodimer formation with the alpha-subunit thus providing experimental confirmation of the conclusions from the crystal structure of the hormone.

A detailed study of the L2beta long-loop region of human chorionic gonadotrophin suggests it to be spatially close to, but not part of, the receptor-binding site.

An in-depth study of the L2beta long-loop region of human chorionic gonadotrophin (hCG), earlier identified to be a conformational bioneutralization epitope and receptor-binding site of the hormone, was carried out. The linear 38-57 hCGbeta peptide and the corresponding cyclic disulphide peptide were synthesized and antipeptide antibodies developed. Binding studies with antibodies to the linear peptide, and with hCGbeta, hCG and human LH suggest that part of the region is buried at the alpha/beta interface and part exposed in hCG. Observation of the surface exposure of residues 47-53 from the crystal structure of hCG was confirmed by epitope mapping studies of the region. The region is not unique to hCG as a majority of the antibodies to both the linear and cyclic peptides did not exhibit the required specificity. Competitive inhibition studies with the linear and cyclic peptides failed to show inhibition of radiolabelled hCG binding to its receptors. However, both the antipeptide antibodies were able to bioneutralize the hormone in an in vivo assay. Taken together, these results seem to indicate that the L2beta long-loop region is not a receptor-binding site of hCG but spatially close to it.

Mapping the receptor binding regions of human chorionic gonadotropin (hCG) using disulfide peptides of its beta-subunit: possible involvement of the disulfide bonds Cys(9)-Cys(57) and Cys(23)-Cys(72) in receptor binding of the hormone.

Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone essential for the establishment and maintenance of pregnancy. The alpha- and beta-subunits of hCG are highly cross-linked internally by disulfide bonds which seem to stabilize the tertiary structures required for the noncovalent association of the subunits to generate hormonal activity. The purpose of this study was to delineate the role of the disulfide bonds of hCGbeta in receptor binding of the hormone. Six disulfide peptides incorporating each of the six disulfide bonds of hCGbeta were synthesized and screened, along with their linear counterparts, for their ability to competitively inhibit the binding of [125I] hCG to sheep ovarian corpora luteal LH/CG receptor. Disulfide peptide Cys (9-57) was found to be approximately 4-fold more potent than the most active of its linear counterparts in inhibiting radiolabeled hCG from binding to its receptor. Similarly, disulfide peptide Cys (23-72) exhibited receptor binding inhibition activity, whereas the constituent linear peptides were found to be inactive. The results suggest the involvement of the disulfide bonds Cys(9)-Cys(57) and Cys(23)-Cys(72) of the beta-subunit of hCG in receptor binding of the hormone. This study is the first of its kind to use disulfide peptides rather than linear peptides to map the receptor binding regions of hCG.

Effect of immunization with synthetic peptide corresponding to region 1-17 of human seminal plasma inhibin on fertility of male rats.

Immunization of adult male rats with a synthetic peptide corresponding to the region 1-17 of human seminal plasma inhibin (hSPI) resulted in agglutination of epididymal sperm, severely affecting the fertility of the animals (75% reduction in fertility as compared to control). This effect was found to be dependent on the antibody titer to hSPI. There was a significant rise in circulating follicle-stimulating hormone levels, with luteinizing hormone and testosterone levels remaining unaffected. The histology of the testes and other reproductive organs revealed that these organs remained unaltered. The N-terminal 1-17 amino acid peptide of hSPI may hold promise as an immunogen for male immunocontraception.

Constraints in the development of contraceptives for men.

Considerable efforts have been made to develop a male contraceptive and the studies have provided very useful information in this field. At least five different strategies to develop a male contraceptive have been pursued, namely: inhibition of sperm production, interference with sperm function, interruption of sperm transport, prevention of sperm deposition, and prevention of sperm-egg interaction. Of all these approaches, inhibition of sperm production by using androgens either alone or in combination with progestins have given the most encouraging results. A number of clinical trials substantiate that it is indeed possible to have a reversible, effective and safe hormonal method of contraception. A postmeiotic and epididymal approach to interfere with sperm function or the secretory and metabolic processes of the epididymis is another attractive option of male contraceptive development. A number of chemical compounds have been identified which interfere with sperm function in the epididymis without affecting sperm production, however, the compounds evaluated so far were found to be toxic. Interruption of sperm transport through the vas either by vasectomy or percutaneous intravasal injection of liquids which form cure-in-place plugs is also an attractive option. However, reversibility of the methods is of concern in their wide scale use. The major constraint in developing a long-acting male contraceptive seems to be the need for greater investment for product development. The clinical trials for evaluating the efficacy and safety of the new products and formulations stretch over several years and require enormous financial commitment. Nevertheless, the long-term gain of having a long-acting reversible contraceptive for men is far greater than the financial commitments over few years. Male attitude towards using methods of family planning is much more favourable than originally believed. The pharmaceutical industry as well as the health care providers therefore have a greater responsibility. For early development of a contraceptive for men, it is essential to increase investment and simplify the drug regulatory procedures. The advent of newer technologies coupled with the convergent efforts of scientists will certainly make it possible to have an effective, safe and reversible male contraceptive in the near future.

Significant intraoperative right ventricular outflow gradients after repair for tetralogy of Fallot: to revise or not to revise?

BACKGROUND: This study was performed to define alternative parameters for the management of intraoperative residual right ventricular outflow obstruction (RVOTO) after transatrial repair of tetralogy of Fallot (ToF) in order to differentiate those requiring immediate revision from those who do not. METHODS: Since October 1995, 166 patients of ToF underwent transatrial repair. Postbypass residual RVOTO was assessed by surgeon's subjective impression, direct intracardiac pressure measurements, and intraoperative echocardiography (IOE). RVOTO was labeled "significant" whenever it exceeded a gradient of 40 mm Hg on IOE or right ventricular to left ventricular pressure ratio (pRV/LV) exceeded 0.85. Further, on IOE, significant RVOTO was defined "fixed", if there was no change in RVOT dimensions during the cardiac cycle, along with the presence of anatomic substrate for obstruction, and "dynamic" if RVOT dimensions increased appreciably in diastole. Postoperative course and follow-up echocardiograms of all patients were analyzed. RESULTS: Significant RVOTO was detected in 58 (35%) patients (mean gradient 54 mm Hg). Seven (12%) of them with fixed obstruction (mean 46 mm Hg) underwent immediate surgical revision, while the remaining 51 patients with mean gradient of 78 mm Hg (including 10 patients with pRV/LV ratio of > or = 1.0) with dynamic obstruction did not undergo revision. There were six (3.6%) early deaths. Operative mortality and postoperative morbidity were not related to higher residual gradients, although the first 15 such patients had longer intensive care stay and inotropic support, in which this was done electively. On follow-up (mean 18.5 months), outflow gradients declined sharply (mean 16 mm Hg) irrespective of the severity of intraoperative gradients (p < 0.001). There were no reoperations or late deaths. CONCLUSIONS: This study shows that: 1) existing parameters for immediate revision of residual RVOTO possibly need to be reviewed; 2) intraoperative echocardiography helps in differentiating "fixed" from "dynamic" obstruction and helps obviate needless revisions; and 3) dynamic RVOT gradients decline significantly irrespective of their severity after transatrial repair of ToF.

Increased male responsibility and participation: a key to improving the reproductive health.

PIP: This article examines the role of male responsibility and participation in the enhancement of reproductive health in India. Men are recognized to be responsible for the large proportion of reproductive ill health suffered by their female partners. Lack of knowledge, nonavailability of acceptable contraceptives and lack of services with quality of care deter men from sharing the responsibility in reproductive health matters. Misinformation regarding male sexuality and limited availability of scientific data contributed men's less involvement in reproductive health. Thus, various strategies are implemented to increase men's awareness of reproductive health and the accessibility of products and services. These strategies include: 1) increasing contraceptive options for men; 2) supporting women's contraceptive use; 3) improving sexual behavior and safe sex practices; and 4) narrowing the gender gap for better fertility control. Moreover, extensive research is required in order to understand men's perceptions and needs about fertility regulation and sexual behavior as well as services development.^ieng

Sevoflurane for induction and intubation in children undergoing congenital cardiac surgery.

The induction and intubation characteristics of sevoflurane were studied prospectively in 23 children, aged 3 months to 6 years (mean 24 +/- 20.25), undergoing repair of congenital cardiac defects. After premedication with syrup chloral hydrate (75mg/kg orally), anaesthesia was induced with 8% sevoflurane and 50% nitrous oxide in oxygen. Nasal endotracheal intubation was performed once the pupils were small and central, without the use of neuromuscular blocking agents or opioids. Characteristics of induction and intubating conditions were recorded. Induction time (from application of face mask to loss of eyelash reflex) was 43.7 +/- 4.57 secs (mean +/- SD). Mean intubation time was 149.1 +/- 15.6 secs. Intubating conditions were excellent in 21 patients (91.3%) and good in 2 patients (80.7%). Haemodynamic parameters (heart rate, rhythm, and systolic blood pressure) were recorded at loss of eyelash reflex, immediately before intubation and at 1, 3 and 5 min after intubation. All children remained haemodynamically stable throughout induction and there were no adverse airway events.