Craniospinal Irradiation in Medulloblastoma using High Energy Medical Linear Accelerator: an Innovative Approach to Planning Technique.

BACKGROUND: Craniospinal irradiation (CSI) of medulloblastoma poses technological challenges due to the involvement of large treatment volume. Commonly, the whole treatment length is covered with two different isocentric plans in which the junction is shifted after every five fractions to overcome the possibility of hot and cold spot. OBJECTIVE: This study aims to evaluate dosimetrically and clinically the innovative planning technique for the CSI which doesn't need re-planning and re-setup of patients after every five fractions. MATERIAL AND METHODS: Computed tomography was done for fifteen (ten children and five adults) patients diagnosed with medulloblastoma. Treatment planning for 36 Gray (Gy) in 20 fractions (#) at the rate of 1.8Gy/# was done on the treatment planning system. A single plan for children was created with two bilateral fields of 6 Mega Voltage (MV) energy for cranium and one posterior field of 6 MV for spinal cord (C1-S2). Two plans for adult patients were created, first plan was with two bilateral fields of 6 MV for cranium and two posterior oblique fields of 6 MV for cervical and the part of thoracic spinal cord (up to T8-T9). The second plan was with a single posterior field of 15 MV covering remaining thoracic (T8-T9 to T12), lumbar and sacrum (up to lower border of S2) spine. After careful evaluation of all the plans, treatment was delivered; acute toxicities were recorded. RESULTS: 95% of prescribed dose was received by more than 95% of planning target volume in all the plans with the acceptable hot spot and good homogeneity index. All the patients reported common radiation induced acute toxicities (headache, vomiting, weakness) during radiotherapy. CONCLUSION: The new planning technique for CSI has acceptable dosimetric and acute clinical possibilities; therefore it can be used for CSI for improved homogeneous dose delivery.

Weight-adjusted tinzaparin for the prevention of venous thromboembolism after bariatric surgery.

Essentials The optimal dose and duration of thromboprophylaxis after bariatric surgery are unclear. We evaluated the safety of weight-adjusted tinzaparin prophylaxis in 1212 patients. In-hospital rates of venous thromboembolism and major bleeding were 0.2% and 1.8% respectively. In a sub-set of patients, trough anti-Xa levels did not show excessive anticoagulant activity. SUMMARY: Background Patients undergoing bariatric surgery are at moderate to high risk of venous thromboembolism (VTE). The optimal dose and duration of anticoagulant prophylaxis is uncertain. Objective To evaluate the safety of extended-duration weight-adjusted tinzaparin after bariatric surgery. Patients/methods We conducted a single-center retrospective cohort study of consecutive patients undergoing bariatric surgery who received weight-adjusted tinzaparin 4500-14 000 IU daily (75 IU kg-1 rounded to the nearest prefilled syringe) for 10 days after surgery (7-9 days post-hospital discharge). Primary safety outcomes were the frequency of VTE and major bleeding within 30 days of surgery in patients receiving at least one dose of tinzaparin. Results A total of 1279 patients undergoing bariatric surgery between July 2009 and December 2012 were reviewed, of whom 1212 received weight-adjusted tinzaparin. Safety outcomes were collected for 819 patients at 30 days, and for 1212 patients in-hospital only. The median age was 45.0 years, median weight was 130.0 kg and 98.8% of patients underwent gastric bypass or sleeve gastrectomy. In patients completing 30 days of follow-up, VTE occurred in 4/819 (0.5%) and major bleeding occurred in 13/819 patients (1.6%). In-hospital rates of VTE and major bleeding during surgical admission were 3/1212 (0.2%) and 22/1212 (1.8%), respectively. Conclusions Extended thromboprophylaxis with weight-adjusted tinzaparin appears to be a safe strategy after bariatric surgery, with low rates of postoperative VTE and major bleeding.

Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1ß and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis (NASH). AIM: To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort. METHODS: A total of 604 adult (≥18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. RESULTS: The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. CONCLUSIONS: These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1ß and IL-6 suppression.

Mesenchymal breast lesions.

Mesenchymal breast lesions encompass a variety of breast diseases. Many of these lesions are rare with only a few case reports in the literature. This article reviews the imaging findings of selected mesenchymal breast lesions, their clinical presentations and method of diagnosis. Mesenchymal lesions are diverse and include haemangioma, granular cell tumour, myofibroblastoma, fibromatosis, pseudoangiomatous stromal hyperplasia, and malignant fibrous histiocytoma. It is important for radiologists to be aware of these lesions as some of them may have malignant potential or demonstrate imaging features that overlap with other malignant lesions.

Carbon monoxide poisoning: a five year review at Tan Tock Seng Hospital, Singapore.

INTRODUCTION: Carbon monoxide poisoning (COP) is one of the leading causes of death from poisoning worldwide. There is no published study of COP in Singapore so far. MATERIALS AND METHODS: All patients admitted with the diagnosis of COP to Tan Tock Seng Hospital (TTSH) over 5 years from 1999 to 2003 were retrospectively reviewed. The diagnosis was based on a history of potential exposure to carbon monoxide (CO) and elevated levels of carboxyhaemoglobin (COHb). The causes, demographic data, clinical presentations, management and complications were analysed. RESULTS: There were 12 patients with COP. Their average age was 38.9 (+/-11.8) years, with a male-to-female ratio of 3:1. Accidental COP (58.3%) was more common than intentional COP (41.7%). The most common cause of accidental COP was smoke inhalation from a faulty vehicle. Gas stove was the most preferred source for intentional poisoning. Presenting features were headache (83.3%), confusion (83.3%), coma (12.7%) and agitation (8.3%). The mean COHb level on admission was 35.9% (+/-13.6). All were treated with 100% oxygen. All the patients achieved normal levels of COHb within 24 hours of admission. Two (16.7%) required intubation for airway protection as they were comatose on arrival, of which 1 presented with very high level of COHb (48.1%) and was the only patient to be treated with hyperbaric oxygen. Acute complications were globus pallidus infarction (16.6%), acute respiratory distress syndrome (8.3%) and myocardial ischaemia (8.3%). Most of the patients (91.7%) were discharged well from the hospital. One patient developed parkinsonism after a follow-up of 2 years. There were no deaths. CONCLUSION: COP is relatively uncommon in Singapore. It has a low rate of short- and long-term complications.

Domain closure and action of uracil DNA glycosylase (UDG): structures of new crystal forms containing the Escherichia coli enzyme and a comparative study of the known structures involving UDG.

The structures of a new crystal form of free Escherichia coli uracil DNA glycosylase (UDG), containing four molecules in the asymmetric unit, and two forms of its complex with the proteinaceous inhibitor Ugi, containing two and four crystallographically independent complexes, have been determined. A comparison of these structures and the already known crystal structures containing UDG shows that the enzyme can be considered to be made up of two independently moving structural entities or domains. A detailed study of free and DNA-bound human enzyme strengthens this conclusion. The domains close upon binding to uracil-containing DNA, whereas they do not appear to do so upon binding to Ugi. The comparative study also shows that the mobility of the molecule involves the rigid-body movement of the domains superposed on flexibility within domains.

The role of leucine 191 of Escherichia coli uracil DNA glycosylase in the formation of a highly stable complex with the substrate mimic, ugi, and in uracil excision from the synthetic substrates.

Uracil DNA glycosylase (UDG), a highly conserved DNA repair enzyme, initiates the uracil excision repair pathway. Ugi, a bacteriophage-encoded peptide, potently inhibits UDGs by serving as a remarkable substrate mimic. Structure determination of UDGs has identified regions important for the exquisite specificity in the detection and removal of uracils from DNA and in their interaction with Ugi. In this study, we carried out mutational analysis of the Escherichia coli UDG at Leu191 within the 187HPSPLS192 motif (DNA intercalation loop). We show that with the decrease in side chain length at position 191, the stability of the UDG-Ugi complexes regresses. Further, while the L191V and L191F mutants were as efficient as the wild type protein, the L191A and L191G mutants retained only 10 and 1% of the enzymatic activity, respectively. Importantly, however, substitution of Leu191 with smaller side chains had no effect on the relative efficiencies of uracil excision from the single-stranded and a corresponding double-stranded substrate. Our results suggest that leucine within the HPSPLS motif is crucial for the uracil excision activity of UDG, and it contributes to the formation of a physiologically irreversible complex with Ugi. We also envisage a role for Leu191 in stabilizing the productive enzyme-substrate complex.

Chimeras between single-stranded DNA-binding proteins from Escherichia coli and Mycobacterium tuberculosis reveal that their C-terminal domains interact with uracil DNA glycosylases.

Uracil, a promutagenic base in DNA can arise by spontaneous deamination of cytosine or incorporation of dUMP by DNA polymerase. Uracil is removed from DNA by uracil DNA glycosylase (UDG), the first enzyme in the uracil excision repair pathway. We recently reported that the Escherichia coli single-stranded DNA binding protein (SSB) facilitated uracil excision from certain structured substrates by E. coli UDG (EcoUDG) and suggested the existence of interaction between SSB and UDG. In this study, we have made use of the chimeric proteins obtained by fusion of N- and C-terminal domains of SSBs from E. coli and Mycobacterium tuberculosis to investigate interactions between SSBs and UDGs. The EcoSSB or a chimera containing its C-terminal domain interacts with EcoUDG in a binary (SSB-UDG) or a ternary (DNA-SSB-UDG) complex. However, the chimera containing the N-terminal domain from EcoSSB showed no interactions with EcoUDG. Thus, the C-terminal domain (48 amino acids) of EcoSSB is necessary and sufficient for interaction with EcoUDG. The data also suggest that the C-terminal domain (34 amino acids) of MtuSSB is a predominant determinant for mediating its interaction with MtuUDG. The mechanism of how the interactions between SSB and UDG could be important in uracil excision repair pathway has been discussed.

Distinct properties of Mycobacterium tuberculosis single-stranded DNA binding protein and its functional characterization in Escherichia coli.

Single-stranded DNA binding proteins (SSBs) play an essential role in various DNA functions. Characterization of SSB from Mycobacterium tuberculosis, which infects nearly one-third of the world's population and kills about 2-3 million people every year, showed that its oligomeric state and various in vitro DNA binding properties were similar to those of the SSB from Escherichia coli. In this study, use of the yeast two-hybrid assay suggests that the ECO:SSB and the MTU:SSB are even capable of heterooligomerization. However, the MTU:SSB failed to complement a Deltassb strain of E. coli. The sequence comparison suggested that MTU:SSB contained a distinct C-terminal domain. The C-terminal domain of ECO:SSB interacts with various cellular proteins. The chimeric constructs between the N- and C-terminal domains of the MTU:SSB and ECO:SSB exist as homotetramers and demonstrate DNA binding properties similar to the wild-type counterparts. Despite similar biochemical properties, the chimeric SSBs also failed to complement the Deltassb strain of E.coli. These data allude to the occurrence of a 'cross talk' between the N- and the C-terminal domains of the SSBs for their in vivo function. Further, compared with those of the ECO:SSB, the secondary/tertiary interactions within MTU:SSB were found to be less susceptible to disruption by guanidinium hydrochloride. Such structural differences could be exploited for utilizing such essential proteins as crucial molecular targets for controlling the growth of the pathogen.

Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.

BACKGROUND: Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown. METHODS: One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation. RESULTS: In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004). CONCLUSIONS: Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.

Differential effects of single-stranded DNA binding proteins (SSBs) on uracil DNA glycosylases (UDGs) from Escherichia coli and mycobacteria.

Deamination of cytosines results in accumulation of uracil residues in DNA, which unless repaired lead to GC-->AT transition mutations. Uracil DNA glyco-sylase excises uracil residues from DNA and initiates the base excision repair pathway to safeguard the genomic integrity. In this study, we have investigated the effect of single-stranded DNA binding proteins (SSBs) from Escherichia coli (Eco SSB) and Mycobacterium tuberculosis (Mtu SSB) on uracil excision from synthetic substrates by uracil DNA glycosylases (UDGs) from E. coli, Mycobacterium smegmatis and M.tuberculosis (referred to as Eco -, Msm - and Mtu UDGs respectively). Presence of SSBs with all the three UDGs resulted in decreased efficiency of uracil excision from a single-stranded 'unstructured' oligonucleo-tide, SS-U9. On the other hand, addition of Eco SSB to Eco UDG, or Mtu SSB to Mtu UDG reactions resulted in increased efficiency of uracil excision from a hairpin oligonucleotide containing dU at the second position in a tetraloop (Loop-U2). Interestingly, the efficiency of uracil excision by Msm UDG from the same substrate was decreased in the presence of either Eco- or Mtu SSBs. Furthermore, Mtu SSB also decreased uracil excision from Loop-U2 by Eco UDG. Our studies using surface plasmon resonance technique demonstrated interactions between the homologous combinations of SSBs and UDGs. Heterologous combinations either did not show detectable interaction (Eco SSB with Mtu UDG) or showed a relatively weaker interaction (Mtu SSB with Eco UDG). Taken together, our studies suggest differential interactions between the two groups (SSBs and UDGs) of the highly conserved proteins. Such studies may provide important clues to design selective inhibitors against this important class of DNA repair enzymes.

X-ray analysis of a complex of Escherichia coli uracil DNA glycosylase (EcUDG) with a proteinaceous inhibitor. The structure elucidation of a prokaryotic UDG.

Uracil-DNA glycosylase (UDG), a key highly conserved DNA repair enzyme involved in uracil excision repair, was discovered in Escherichia coli . The Bacillus subtilis bacteriophage, PBS-1 and PBS-2, which contain dUMP residues in their DNA, express a UDG inhibitor protein, Ugi which binds to UDG very tightly to form a physiologically irreversible complex. The X-ray analysis of the E. coli UDG ( Ec UDG)-Ugi complex at 3.2 A resolution, leads to the first structure elucidation of a bacterial UDG molecule. This structure is similar to the enzymes from human and viral sources. A comparison of the available structures involving UDG permits the delineation of the constant and the variable regions of the molecule. Structural comparison and mutational analysis also indicate that the mode of action of the enzyme from these sources are the same. The crystal structure shows a remarkable spatial conservation of the active site residues involved in DNA binding in spite of significant differences in the structure of the enzyme-inhibitor complex, in comparison with those from the mammalian and viral sources. Ec UDG could serve as a prototype for UDGs from pathogenic prokaryotes, and provide a framework for possible drug development against such pathogens with emphasis on features of the molecule that differ from those in the human enzyme.

Rapid and reliable site directed mutagenesis using Kunkel's approach.

Oligonucleotide based site directed mutagenesis (SDM) is an invaluable technique in molecular biology. Among the various methods developed for SDM, the PCR-based approach, Kunkel's and the Eckstein's procedures are widely used. The Kunkel's method, on account of its cost effectiveness and simplicity, is preferred by many a scientist. However, a general drawback of this method is the high background due to persistence of the parent template resulting in low efficiency of mutagenesis. In this report, we describe a modification of the Kunkel's method to increase the efficiency of selecting against the wild type strand. We have used Sequenase for the extension reaction, and introduced an in vitro UDG step to enhance the biological selection against the parent strand. Consequently, the efficiency of the modified method is enhanced to allow screening of the mutants directly by DNA sequencing. A step by step single tube protocol which is over in less than three hours makes it a method of choice for efficient and cost-effective site directed mutagenesis.

Use of a coupled transcriptional system for consistent overexpression and purification of UDG-Ugi complex and Ugi from Escherichia coli.

We have designed a novel coupled transcriptional construct wherein Escherichia coli uracil DNA glycosylase (UDG) and Bacillus subtilis phage PBS-2 encoded uracil DNA glycosylase inhibitor protein (Ugi) genes were cloned in tandem, downstream of an inducible promoter (Ptrc). Use of this bicistronic operon has allowed purification of large amounts of UDG-Ugi complex formed in vivo. The system has also been exploited for purification of large amounts of Ugi. While establishing the expression system, one of the constructs showed detectable suppression of UAG termination codon and resulted in accumulation of a minor population of a putative readthrough polypeptide corresponding to UDG. We discuss the likely occurrence of such a phenomenon in overproduction of other recombinant proteins. Finally, the usefulness of the operon construct in convenient mutational analysis to study the mechanism of UDG-Ugi interaction is also discussed.

Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group.

BACKGROUND: There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events. METHODS: The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up. RESULTS: No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035). CONCLUSIONS: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group.

BACKGROUND: The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. METHODS: Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. RESULTS: The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients (0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA (P=NS). Serum creatinine rose transiently in 35 patients (9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA (P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA (P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug (P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). CONCLUSIONS: MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Asymptomatic axial torsion of the pregnant uterus: a cause of the failure of induction of mid-trimester abortion.

Torsion of gravid uterus is a rare obstetric condition in which diagnosis is usually made only on laparotomy. A case of asymptomatic axial torsion of uterus during mid-trimester, because of an ovarian cyst is reported. This presented as a failure of induction of abortion by extra-amniotic isotonic saline instillation and oxytocin infusion.

A study of perinatal mortality rate from rural based Medical College Hospital.

PIP: This study was conducted at a rural medical college and aimed at analysis of the perinatal mortality and its determinants in a rural environment. 58 stillbirths and 62 early neonatal deaths among 1107 consecutive deliveries effected a perinatal mortality rate of 108.4/1000 deliveries. 50% of the total deliveries were unbooked. The perinatal mortality was higher in unbooked cases (16.3%), twins (33.2%), and preterm deliveries (33.9%) as compared to that in booked cases (5.3%), singletons (9.6%), and term deliveries (6.7%). 69% of the stillbirths were the result of obstructed labor, toxemia, antepartum hemorrhage, hand prolapse, and cord prolapse where timely intervention would have reduced the perinatal mortality significantly. Early neonatal deaths were mainly associated with prematurity and were due largely to birth anoxia, intraventricular hemorrhage, aspiration, and infections.^ieng