Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective.

CYP1A1 gene is involved in estrogen metabolism, and previously, we have reported association of variant rs2606345 with altered anti-epileptic drugs (AED) response in North Indian women with epilepsy (WWE). The present study aims to replicate the pharmacogenetic association, perform functional characterization and study its distribution within ethnically diverse Indian population. The variant was genotyped in 351 patients to assess the pharmacogenetic association and 552 healthy individuals belonging to 24 different ethnic groups to examine the distribution in Indian population. We observed significant overrepresentation of 'A' allele and 'AA' genotype in poor responders in WWE at Bonferroni-corrected significance levels. The recessive allele was found to lower the promoter activity by ~70-80% which was further substantiated by thermally less stable hairpin formed by it (ΔTm=7 °C). Among all ethnic groups, west Indo-European (IE-W-LP2) subpopulation showed highest genotypic frequency of the variant making women from this community more prone to poor AED response. Our results indicate that rs2606345 influences drug response in WWE by lowering CYP1A1 expression.

Cytogenetic, Y chromosome microdeletion, sperm chromatin and oxidative stress analysis in male partners of couples experiencing recurrent spontaneous abortions.

PURPOSE: Etiology in majority of couples experiencing recurrent spontaneous abortions (RSA) is still unknown. The aim of the study was to find the role of cytogenetic abnormalities, Y chromosome microdeletion, oxidative stress (OS) and sperm DNA fragmentation in male partners of couples experiencing RSA. METHODS: Forty-eight couples with history of RSA and 20 fertile controls were included in the study. The study subjects were divided into male partners of RSA couples with abnormal sperm parameters (SA) (N = 16), male partners of RSA couples with normal sperm parameters (NS) (N = 32) and age-matched fertile controls with normal sperm parameters (FC) (N = 20). RESULTS: One of 48 men (2%) showed 46, XY (1qh-) chromosomal complement. None of the cases including FC showed deletion in any of the 3 AZF loci on Y chromosome long arm. Sperm count was found be significantly lower in SA cases as compared to group NS cases (P < 0.0001) and FC (P < 0.005). Sperm forward motility was found to be significantly (P < 0.05) lower in SA cases as compared to NS and FC. Male partners of RSA couples with abnormal sperm parameters had higher reactive oxygen species (ROS) levels (P < 0.005) and sperm DNA damage (P < 0.0001), however, in male partners of RSA couples with normal sperm parameters had only increased (P < 0.0001) sperm DNA damage. CONCLUSION: Other than chromosomal anomalies, sperm DNA fragmentation and seminal OS may be the underlying pathology in RSA, thus screening for seminal ROS levels and DNA fragmentation has diagnostic and prognostic capabilities.

A comprehensive work up for an asthenozoospermic man with repeated intracytoplasmic sperm injection (ICSI) failure.

Infertility affects about 15-20% couples attempting pregnancy and in about half cases the problem lies in the male. Among the sperm parameters, linear progressive motility is one of the most important predictors of fertility potential. Though genetic and chromosomal abnormalities are important aetiological factors in the pathogenesis of male infertility, the mechanism involved in impaired sperm motility is poorly understood. Here we report mitochondrial DNA (mtDNA) mutations with increased seminal reactive oxygen species (ROS) levels and higher DNA fragmentation level in the sperm resulting in decreased ATP production which plays an important role in sperm motility defect. Thus it is important to understand the aetiology of asthenozoospermia and to distinguish if infertile men harbour nuclear or mtDNA mutation as they are very important prognostic markers. This case study also highlights that routine semen parameters are very modest predictors of fertility outcome but ROS estimation and DNA integrity analysis by Comet assay have better diagnostic and prognostic capabilities. Thus this study is a detailed and comprehensive workup of an infertile asthenozoospermic male.

Antioxidant levels in blood and seminal plasma and their impact on sperm parameters in infertile men.

Excess reactive oxygen species (ROS) beyond the scavenging capacity of antioxidants leads to DNA damage and oxidation of lipoprotein components at the cellular and subcellular level. The oxidative stress (OS) adversely affects sperm function by altering membrane fluidity, permeability and impairs sperm functional competence. In the present study, the OS status in seminal plasma and blood serum in infertile men and its relationship with spermatozoa parameters have been investigated. Four groups of infertile men viz., oligozoospermic (n = 15), asthenozoospermic (n = 17), teratozoospermic (n = 19), and oligoasthenoteratozoospermic (n = 9), and healthy fertile controls (n = 40) have been analyzed for superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA) in seminal plasma and blood serum. Significant correlation between blood serum SOD and sperm count has been observed in patients (p = 0.018) and controls (p = 0.021). Similarly, significant correlation between blood serum GSH and sperm progressive motility in patients (p = 0.036) and controls (p = 0.029) is observed. The low seminal MDA is associated with increase in sperm progressive motility in patients (p = 0.039) and controls (p = 0.028). Positive correlation is found between increased seminal MDA levels and abnormal sperm morphology in both patients and controls (r = 0.523, p = 0.029; r = 0.612, p = 0.034 respectively). Correlations between blood SOD and sperm count and between blood GSH levels and progressive motility suggest that these can be important biochemical markers in assaying the sperm count and motility. A negative correlation of motility with seminal MDA indicates that sperm membrane lipid peroxidation affects the fluidity and thus mobility of sperm axoneme. This affects functional competence of the sperm and acts like a biological safeguard. The results of the present study suggest the prospects of using the blood serum and seminal plasma antioxidants as a valuable tool to evaluate the sperm reproductive capacity and functional competence.

Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency.

PURPOSE: Primary ovarian insufficiency (POI) is a heterogeneous, multifactorial disorder. Though genetic anomalies, infections, autoimmune disorder and hormonal imbalance are few of the causes of POI, in the majority of patients (50-60%) no etiology has been identified. Mitochondrial bioenergetics and biogenesis play an important role in oocyte and embryo development, whereas mtDNA integrity and content are essential for the normal development of oocytes. ATPase6 helps to maintain the mt genome integrity, and mutations in ATPase6 are associated with overproduction of reactive oxygen species (ROS) in a variety of diseases; however, its role in POI has not been evaluated. Therefore, we planned to evaluate the potential role of ATPase6 gene mutations and associated oxidative stress in idiopathic cases of POI. METHODS: This pilot study included: 20 cases of POI with FSH level of >40 mIU/ml; 4 cases of occult ovarian insufficiency (occult OI) with irregular menses and mean FSH levels of 16.4 mIU/ml; and 20 age-matched healthy female controls (FSH 2-5 mIU/ml). ROS levels in blood plasma were measured by luminol-dependent chemiluminescence assay and the ROS values were expressed as relative light unit per minute (RLU/min). mtDNA ATPase6 gene was amplified and sequenced from the blood lymphocyte DNA. RESULTS: Of all, 50% patients showed nucleotide changes in the ATPase6 gene, as compared to 10% in controls, and the majority of these mutations were non-synonymous. ATPase6 mt.8684 C>T and mt.9094 C>T were found to be significantly (P < 0.005) higher in cases as compared to controls. ROS levels were found to be significantly (P < 0.005) higher in POI and occult OI patients compared to controls and nucleotide changes were found to positively correlate with ROS levels. Moreover, ROS production was found to positively correlate (r = 0.7038, P < 0.001) with FSH levels of the patients (POI and OI) compared to controls. CONCLUSIONS: This pilot study clearly demonstrates for the first time ATPase6 gene nucleotide alterations and elevated ROS levels in idiopathic cases of POI. Therefore, it may be possible that OS associated with ATPase6 gene mutation may be causal in idiopathic cases of premature OI. However, larger studies with inclusion of more cases of both POI and occult OI are required to strongly establish the correlation between oxidative stress and mitochondrial nucleotide alterations in the pathogenesis of POI. Such cases with OS-induced POI may benefit immensely by early diagnosis and prompt antioxidant administration.

Profile of Live-born Infants of In-vitro Fertilisation.

INTRODUCTION: The Army Hospital (R&R) is the only service hospital providing in-vitro fertilisation (IVF) facility. Neonatal characteristics of live-born infants at this centre over a two-year period are analyzed in this study. METHODS: Data on 504 consecutive live-born IVF infants over a two-year period (01 Feb 2007 to 31 Jan 2009) were analysed. RESULT: Of the 504 neonates, 190 (37.7%) were born by vaginal delivery, 156 (30.9%) by elective lower segment cesarean section (LSCS) and 127 (25.19%) following emergency LSCS. Maternal illness posing specific risk to the neonate was present in 165 out of 504 (32.7%). There were 239 (47.4%) preterm neonates. Males formed 51.8% of the cohort. Singletons accounted for 51.2%, while the rest (48.8%) were products of twin pregnancies. Small for gestational age neonates formed 22.6% (n = 114). A total of 20 (3.9%) infants had congenital malformations. There were 242 (48.1%) low birth weight neonates. A total of 128 (25.4%) neonates needed neonatal intensive care. Of the 504, there were 474 (94.1%) survivors while 30 (5.9%) did not survive. Twenty-nine (6.1%) neonates required readmission during the neonatal period. CONCLUSION: In our setting, neonates born following IVF appeared to be at increased risk of prematurity, multiple births and low birth weight. Proper obstetric and neonatal management can result in good neonatal outcomes.

Oxidative stress and sperm mitochondrial DNA mutation in idiopathic oligoasthenozoospermic men.

Physiological function of reactive oxygen species (ROS) has been known since a long, but recently toxic effects of ROS on spermatozoa have gained much importance in male infertility. Mitochondrial DNA (mtDNA) is believed to be both source and target of ROS. mtDNA unlike nuclear DNA is not compactly packed and hence more susceptible to oxidative stress (OS) than nuclear DNA. In the present study, the role of OS in mitochondrial genome changes was studied in men with idiopathic infertility. The study included 33 infertile oligo-asthenozoospermic (OA) men and 30 fertile controls. Semen analyses were performed and OS was measured by estimating the level of malondialdehye (MDA) in the seminal plasma and ROS in the sperm. Sperm mtDNA was sequenced by standard PCR-DNA sequencing protocol for ATPase and nicotinamide adenine dinucleotide dehydrogenase (ND) groups of genes. Sperm count and progressive motility were found to be significantly lower in infertile group than the fertile controls. Semen MDA and ROS levels of infertile group were significantly higher (p<0.0001), when compared to the control group. However, catalase and glutathione peroxidase (GPx) levels were significantly lower in infertile group, compared to controls, but no significant difference in superoxide dismutase (SOD) activity was observed between control and cases. This might be due to higher expression of SOD alone in order to overcome OS in the semen. mtDNA analysis showed significant and high frequency of nucleotide changes in the ATPase (6 and 8), ND (2, 3, 4 and 5) genes of infertile cases compared to the controls. Hence excess ROS and low antioxidant levels in the semen might cause mtDNA mutations and vice versa in OA men that might impair the fertilizing capacity of spermatozoa. Thus, it is important to understand the etiology of mitochondrial genome mutations in idiopathic OA cases for better diagnostic and prognostic value in infertility treatment/assisted reproductive technique.

DNA integrity and semen quality in men with low seminal antioxidant levels.

Accurate transmission of information coded in the sperm genome is vital to the pre- and post-natal development of the offspring. Recent advances in reproductive biology have proposed evaluation of sperm DNA integrity as an important assessment tool to infer the presence of DNA strand breaks, numerical abnormalities in sperm chromosome complement, and alterations in the epigenetic regulation of the paternal genome. Oxidative stress (OS), characterized by increased free radicals, may lead to the production of apurine sites, apyrimidine sites, oxidation of nucleotides of sperm genome. This study was performed to assess the impact of OS on DNA integrity in sperms. 52 infertile men [oligozoospermic-13, asthenozoospermic-15, teratozoospermic-19, oligoasthenoteratozoospermic-5] and 20 fertile controls were investigated for products of lipidperoxides as malondialdehyde; antioxidants such as superoxide dismutase, catalase and glutathione in seminal plasma by biochemical methods. DNA integrity of the sperms was analyzed by visual scoring method in which the comets were graded into 4 categories (A-D) on the basis of their tail length indicative of increasing levels of DNA damage. Significant increase in DNA damage (higher number of sperms in group D) in cases (oligozoospermic (O)-20%, asthenozoospermic (A)-24%, teratozoospermic (T)-28%, OAT-43%) as compared to controls (8%) was found. Increased malondialdehyde levels, abnormal sperm morphology and higher DNA damage were observed in the cases. The antioxidants superoxide dismutase, catalase and glutathione had a positive association with sperm count and motility while a negative association with the percentage of dead sperms and abnormal morphology was observed. This study highlights the influence of low antioxidants on sperm genome integrity and indicates sperm DNA integrity as a better and more reliable prognostic tool for infertility evaluation than simple quantitative and morphologic evaluation of spermatozoa.

The family and peer group influences in aggression.

This study attempts to find a relationship between factors in the family, peer group, and levels of adolescent aggression. 148 adolescents and their mothers were studied. It was found that negative parenting and exposure to deviant peers influenced aggression among the adolescents.

Effect of active immunization against luteinizing hormone-releasing hormone on the androgen-sensitive Dunning R3327-PAP and androgen-independent Dunning R3327-AT2.1 prostate cancer sublines.

BACKGROUND: The objective of this study was to determine the effect of active immunization against LHRH on the growth characteristics and histology of subcutaneously implanted tumors of the androgen-sensitive Dunning R3327-PAP and androgen-independent R3327-AT2.1 rat prostate adenocarcinoma sublines. RESULTS: We herein demonstrate that 1) active immunization with an LHRH-diphtheria toxoid-conjugate (LHRH-DT) leads to the downregulation of gonadotropins and testosterone and consequently the atrophy of testosterone-dependent organs such as the testes, prostate, and androgen-sensitive Dunning R3327-PAP tumors, 2) growth inhibition of Dunning R3327-PAP tumors is caused by suppression of cell division rather than by an increase in cell death and is associated with an increase of the tumor stroma content, and 3) volume increase of the androgen-independent Dunning R3327-AT2.1 tumor is slightly but significantly reduced, indicating a local stimulatory LHRH loop within this tumor cell line.

An analytical framework for the study of proximate determinants of maternal mortality.

PIP: A country's level of maternal mortality is a sensitive index of the provision and quality of health and obstetric services. It is important to understand the determinants of maternal mortality in order to take measures which will effectively quicken the pace of its decline. The authors present an analytical framework of factors which affect the risk of maternal mortality, using an epidemiological approach adopted to identify risk factors at the microlevel. The relative risk of each key factor was then estimated based upon empirical data using odds ratio. The study population was comprised of all 252 maternal deaths and 252 matched maternal survivors at Safdarjung hospital, New Delhi, between January 1, 1983, and December 31, 1985. Cases and controls were matched by age, parity, and registration status for antenatal care. The empirical findings of the study are consistent with the notion that maternal mortality is affected by demographic, socioeconomic, medical, and obstetric factors.^ieng

Laboratory techniques for diagnosis of chlamydial infections of the eye.

Giemsa and fluorescence antibody (FA) staining were used to diagnose patients clinically suspected to be suffering from trachoma. A total of 52 controls i.e. individuals with refractive errors and no clinical trachoma and 173 cases suffering from different stages of trachoma were studied. FA was found to be 2.52 times more sensitive in confirming the presence of Chlamydia trachomatis compared to Giemsa staining. 28/52 (53.8%) and 4/52 (7.,69%) controls were also positive by FA and Giemsa staining, respectively, indicating sub-clinical infection without symptoms. Post treatment staining with both methods revealed that clinical cure of trachoma did not necessarily mean the absence of Chlamydia trachomatis in the conjunctival smears. As a corollary it can be deduced that mere presence of Chlamydia trachomatis in conjunctival epithelial cells may not cause clinical trachoma, certain host factors (local immunity etc.) may play an important role in clinical disease.

Secondary fungal infections in chronic suppurative otitis media.

A clinical, bacteriological and mycological study of 103 cases of 'safe' chronic suppurative otitis media with intractable otorrhoea was conducted to observe the role of fungi in the pathogenesis and perpetuation of the disease process. Mycotic otitis media was found in 42 cases (40.77%).45 patients with draining ears which grew pure bacterial growth were treated with ear drops. Fifteen of these patients were treated with topical antibiotics (polymyxin, Neomycin & Gramicidin). Other 15 patients were put on antibiotic steroid (Polymxin, Neomycin and Hydrocortisone) ear drops. The remaining 15 patients acted as controls with dry mopping treatment only.It was noted that prolonged exposure to antibiotic ear drops and antibiotic-steroid ear drops led to the growth of pathogenic fungi in 5 patients (33.33%) each from two study subgroups while the third control subgroup of 15 patients grew fungi of low virulence in 3 cases (20%).It was concluded that the routine and prolonged use of topical antibiotics or antibiotics-steroids in cases of wet 'safe' chronic suppurative otitis media, from the onset is not justified.

Candida overgrowth after treatment of duodenal ulcer. A comparison of cimetidine, famotidine, and omeprazole.

Acid-reducing drugs can cause increased growth of microbes, including fungus, because of high gastric pH. Our purpose was to evaluate the occurrence of mycotic infection in patients with duodenal ulcer on anti-ulcer therapy and to compare the effects of cimetidine, famotidine, and omeprazole. Eighty patients with duodenal ulcer (62 males and 18 female patients, 16-65 years old) were evaluated for mycotic infection before and after 6 weeks of therapy (cimetidine, 20 patients; famotidine, 40 patients; omeprazole, 20 patients). Mycotic infection was diagnosed by endoscopic biopsy from the ulcer edge subjected to smear, culture, and histopathology and by endoscopic brush samples and gastric aspirate. On the basis of these studies, patients were categorized as having no fungal growth, saprophytic growth, or significant fungal growth. Thirty-five (43.8%) patients had evidence of fungus before ulcer therapy, and 16 of the 35 (20%) had significant fungal growth. The fungal isolation rate was higher in older patients (> and = 45 years of age) and in those with an ulcer size > and = 2 cm. While there was no significant increase in the total number of patients with evidence of fungus after therapy (n = 36), there was a significant increase in those with significant growth (n = 27, p < 0.05) compared with pretreatment status. We found that posttreatment gastric pH of > and = 4 was associated with a higher fungal positivity rate (59.4%) than pH values < 4 (32.4%, p < 0.05). However, neither the type of drug used nor the response in terms of ulcer healing correlated with the presence of fungus. Regardless of the type of drug used, acid-reducing therapy is associated with increased significant fungal growth.

Fungal colonization of untreated peptic ulcer.

AIM: To evaluate the relationship between Candida and peptic ulcer. METHODS: One hundred consecutive patients with untreated peptic ulcer (81 with duodenal ulcer and 19 with gastric ulcer) were studied using histopathology, culture and fungal serology. Twenty subjects with non-ulcer dyspepsia were taken as controls. RESULTS: Forty seven patients (47%) with peptic ulcer were colonized by Candida as compared to 3 patients (15%) with non ulcer dyspepsia (p < 0.05). Confluent growth of Candida on culture of gastric aspirate or biopsy from ulcer edge was a more sensitive method for diagnosis of peptic ulcer-associated candidiasis than histological examination. There was no significant difference in the prevalence of Candida isolation in relation to age or sex of the patients, smoking habit and alcoholism. Large ulcers (> 2 cm) were, however, more often colonized by Candida (75%) than smaller ones (43%) (p < 0.05). Candida albicans was the commonest species isolated (60%). Invasive candidiasis was associated with Candida agglutinin titer of 1:128 in 81% of cases. CONCLUSION: Candida colonization rate in peptic ulcer is significantly higher than in non-ulcer dyspepsia.

Population profile of India: past, present and future.

PIP: India's 846.3 million people, who comprise 16% of the world population, inhabit just 2.4% of the total world area. India is the 2nd most populous country in the world. 74% of people live in 600,000 villages that follow traditional social and cultural practices. Population growth peaked during 1961-1981 at 2.2%/year. It began to fall slightly during 1981-1991 to 2.1%/year. Even though those younger than 15 years old comprise the largest population age group (39.6%), the group is decreasing (42% in 1971). India's dependency ratio is 0.9 for both children and the elderly and 0.8 for children alone. India has an excess number of males (929 females/1000 males), due largely to discrimination against females. Pregnancy and child birth are responsible for female death rates peaking at ages 15-29. Delayed marriages are more common than in the past (6.6% in 1981 and 19% in 1961). Most internal migration is from rural area to rural area (especially for females leaving their parents' home to go to that of their husband's) and rural area to urban area. Population density varies by state from 10 people/sq. km. to 6319 people/sq. km (mean = 267/sq. km.). Total fertility is 3.9 in rural areas and 2.7 in urban areas. 71% of births have a birth interval of less than 3 years. The 1985-1990 death rate in India compares to that of developed countries (9.8 vs. 10), but its infant mortality rate is still high (79 vs. 15). The population projections for 2001-2006 of the Standing Committee on Population Projections are 1003.1 million for population size, 23 for birth rate and 7.8 for death rate. It expects the population to stabilize (i.e., 0 growth rate) at 1.5 billion around 2080. This figure is much less than that of the World Bank's projection.^ieng

Incidence of cryptococcosis in and around Chandigarh, India, during the period 1982-91.

The incidence of cryptococcosis was evaluated in and around Chandigarh, India over a period of 10 years (1982-91). Different species of Cryptococcus were isolated from 38 patients. Cryptococcus neoformans was the predominant isolate (26 = 68%) followed by Cr. albidus (2), Cr. laurentii (1) and not precisely identified Cryptococcus species (9 = 24%). Serotyping of the 18 isolates of Cr. neoformans revealed that 13 (72%) were serotype A, two (11%) were serotype AD and three (17%) were serotype B (Cr. neoformans var. gattii). Cryptococcus species were found to produce infection in 24 patients and were possibly transient colonizers in another 14 patients. In addition, in 11 patients no Cryptococcus species was isolated from any site but the latex agglutination test for antigen (Crypto-LA) was positive in serum and/or cerebrospinal fluid. Response to various antifungal drugs was also studied in these patients.

Management of high risk mothers and maternal mortality in Indian population.

PIP: The logistic model used in this study revealed a 0.99923 probability of maternal mortality associated with severe anemia, hemorrhage, and pregnancy-induced hypertension. Sensitivity of the model was 89.47%, and accuracy of prediction was 80.7% Other risk factors included in the regression were sepsis, hyperpyrexia, and birth interval. The study sample included 252 maternal deaths occurring between January 1, 1983, and December 21, 1985, at Safdarung Hospital in New Delhi, India, matched to controls; multivariate analysis was performed with 57 matched cases. The risk of anemia alone was nine times higher among women with this history. The adjusted odds ratio with severe anemia and controlling for pregnancy-induced hypertension increased to 9.151. The odds ratio for severe anemia when controlling for pregnancy-induced hypertension and hemorrhage was 8.783. The odds ratio with severe anemia and controls for hemorrhage, hyperpyrexia, and short birth interval was 9.980. The odds ratio with severe anemia and controls for hemorrhage, hyperpyrexia, short birth interval, and pregnancy-induced hypertension was 9.945. With severe anemia and controls for the remaining five risk factors, the odds ratio was 7.010. Management of high-risk mothers should reduce maternal mortality.^ieng

High mortality in systemic fungal infections following renal transplantation in third-world countries.

Amongst 310 recipients of live related renal transplants, systemic fungal infections were observed in 19 patients (6.1%). These included cryptococcosis in eight (42%), candidiasis in seven (37%), mucormycosis in two (11%), aspergillosis in one (5.5%), and a mixed cryptococcal and Aspergillus infection in one patient (5.5%). Infections occurred within 12 months of transplantation in seven patients and after 13-37 months in the remaining patients. Prolonged fever not responding to antibiotics was the most common presentation. Central nervous system was involved in all patients with cryptococcosis, while Candida infection primarily involved the urinary tract. Both patients with mucormycosis exhibited signs and symptoms of florid rhinocerebral disease and a rapid downhill course. Pulmonary manifestations were the most prominent features of patients with aspergillosis. Parenteral amphotericin B with or without 5-fluorocytosine was started in all, but three patients could receive the therapy only for 1-3 weeks. Three patients with cryptococcosis developed amphotericin-related complications and were changed to oral fluconazole. Seven patients recovered and 12 (63%) died. None of the patients had cytomegalovirus infection preceding the onset of fungal disease. The high frequency of fungal infections amongst our allograft recipients could not be ascribed to over immunosuppression, since 16 patients (84%) were only on maintenance doses of immunosuppressive drugs and in 13 (68.4%) graft function was normal at the time of diagnosis. The high frequency of fungal infections in our patients was most probably related to the poor hygienic and sanitary conditions which continue to be prevalent in the tropical environment of third-world countries. Delays in the diagnosis and late institution of therapy result in a high mortality.(ABSTRACT TRUNCATED AT 250 WORDS)