Heterogeneous disease modeling for Hardy-Weinberg disequilibrium in case-control studies: application to renal stones and calcium-sensing receptor polymorphisms.

Renal stone formation due to hypercalciuria is a relatively common disorder with clear evidence for genetic predisposition, but cryptic phenotypic heterogeneity has hampered identification of candidate genes. The R990G single-nucleotide polymorphism (SNP) of the calcium sensing receptor (CASR) gene has been associated with hypercalciuria in stone formers and shows the appropriate functional phenotype in cell culture. In our preliminary association analysis of a case-control cohort, however, we observed significant Hardy-Weinberg disequilibrium (HWD) for the cases (n= 223), but not controls (n= 676) at the R990G locus, pointing us toward the general disease model incorporating HWD. Because there is an adjacent CASR SNP, A986S, which is in negative linkage disequilibrium with R990G, we extended the general disease model to enable testing of a two-site hypothesis. In our data set, there is no lack of fit (P= .345) for the single-locus model for the R990G genotype, and likelihood ratio testing favors a recessive effect with an eight-fold increase in risk (P < .001) for GG homozygotes, relative to wild-type, based on a population prevalence of 2%. Addition of the A986S genotype provides no additional information either by itself or when included in our two-site model.

Efficacy of orally disintegrating ondansetron in preventing postoperative nausea and vomiting after laparoscopic cholecystectomy: a randomised, double-blind placebo controlled study.

Peri-operative prophylactic anti-emetics are commonly used parenterally. Orally disintegrating ondansetron is efficacious during chemotherapy. Therefore, we aimed to study the efficacy of orally disintegrating ondansetron for postoperative nausea and vomiting. In a randomised, double-blind, placebo controlled trial on 109 patients scheduled for laparoscopic cholecystectomy, oral ondansetron was compared to intravenous ondansetron and placebo. The anaesthetic technique was standardised. Mean time (SD) to tolerating oral intake was delayed in the placebo group to 366.1 (77.6) min compared to oral 322.9 (63.7) min and intravenous 322.4 (65.2) min groups. This is corroborated by a higher incidence of nausea and vomiting in the control group during the first 6 h postoperatively (control 44.4%, oral 17.7%, intravenous 18.2%). There was no significant difference between oral and intravenous groups. In conclusion, orally disintegrating ondansetron was as efficacious as intravenous ondansetron in the peri-operative phase and may be a viable option for prophylaxis of emesis in day care surgery.

A single dose of preoperative gabapentin for pain reduction and requirement of morphine after total mastectomy and axillary dissection: randomized placebo-controlled double-blind trial.

BACKGROUND: Gabapentin has been recently found to be useful for reducing acute postoperative pain when administered preoperatively. Although various dose regimens have been tried in different surgical settings, the minimum effective dose is not established. AIMS: We aimed to evaluate the analgesic efficacy of single low dose gabapentin in patients undergoing total mastectomy and axillary dissection. SETTINGS AND DESIGN: Prospective randomized placebo-controlled double-blind trial in a tertiary care teaching hospital. MATERIALS AND METHODS: Fifty women scheduled for total mastectomy and axillary dissection were randomized to receive either gabapentin 600 mg or placebo orally 1 h preoperatively. The intraoperative and postoperative management was standardized. Postoperative pain was assessed at rest and on movement for 12 h using the numerical rating scale (NRS). Morphine was administered if NRS exceeded 30. Primary outcome measure was total morphine consumption. STATISTICAL ANALYSIS: The morphine consumption was compared using independent t test while pain and sedation scores were analyzed using Mann-Whitney U test. RESULTS: Forty-six patients completed the trial. The postoperative morphine consumption was significantly less (5.8 +/- 4.2 vs. 11.0 +/- 3.4 mg; P 0.001) and the median [IQR] time to first analgesic was significantly longer (90 [37.5-120] vs. 0 [0-90] min; P 0.001) in the gabapentin group than in the placebo group. The incidence of side effects was similar in the two groups. CONCLUSIONS: A single low dose of 600 mg gabapentin administered 1 h prior to surgery produced effective and significant postoperative analgesia after total mastectomy and axillary dissection without significant side effects.

Assessment of the effectiveness of peripheral administration of fentanyl with lidocaine in inflamed dentoalveolar tissues.

Peripheral action of opioids for pain control, for which local inflammation has been shown to be crucial, is being increasingly used in clinical practice. The aim of this study was to evaluate the hypothesis that addition of fentanyl to lidocaine, when injected into inflamed dentoalveolar tissues, can improve the quality of analgesia during surgery. Seventy-one patients reporting with pain and tenderness in the maxillary tooth were assigned into the experimental (LAF) or control (LA) group in a prospective, randomized double-blind trial. The LAF group (n = 36) was injected submucosally with a mixture of 40 microg of fentanyl (0.8 ml) and 2% lidocaine hydrochloride with 1:200000 adrenaline (2 ml). In the LA group (n = 35) 0.9% of saline (0.8 ml) was added instead of fentanyl. The pain scores were recorded before injecting, 5 min after injection, and immediately after surgery using a visual analogue scale. The mean pain scores were not significantly different at all time intervals. Twelve patients in the LAF group (2.75+/-0.72 ml) and ten patients in the LA (2.90+/-0.70 ml) group required additional local anaesthetic to achieve pain control. In conclusion, there was no improvement in quality of intraoperative analgesia on addition of fentanyl to lidocaine in inflamed dentoalveolar tissues.

Prevalence of weight gain in patients with better renal transplant function.

AIMS: This study investigates the association between renal function and change in weight after kidney transplantation. METHODS: Retrospective analyses of 165 transplant patients on maintenance steroids who were followed-up for 6.2 +/- 2.4 years. RESULTS: 101 males and 64 females participated in the study. Results are expressed as mean +/- SD. At the first post-transplant outpatient visit (time 0), BMI was 25.3 +/- 4.8 kg/m2. It increased significantly by 7.7 +/- 10.8% and 10.9 +/- 12.6% at 1 and 5 years. 18 and 29% of patients had a BMI > 30 kg/m2 at times 0 and 5 years, respectively. Thereafter, diminishing glomerular filtration rate (GFR) was associated with the loss of the excess weight. Multivariate analysis showed that GFR, but not age, race, sex, source of graft, number of HLA mismatches or length of dialysis was significant to post-transplant weight gain. 38 patients gained weight > 1 SD above the mean of the population and were designated the high weight gain (HWG) group. 41 patients gained weight < the mean - 1 SD of the population and were designated the low weight gain (LWG) group. GFR in the high and low weight gain groups at time 0 was 71.8 +/- 20.3 ml/min/1.73 m2 and 66.4 +/- 23.1 ml/min/1.73 m2, respectively (p = NS), as compared to 77.4 +/- 23.3 ml/min/1.73 m2 and 61.5 +/- 24.5 ml/min/ 1.73 m2 at 6 months, respectively (p < 0.01) and continued to be significant thereafter (72.7 +/- 17.2 ml/min/1.73 m2 and 58.9 +/- 19.8 ml/min/1.73 m2, p < 0.05 at 6 years). CONCLUSIONS: Patients with relatively better renal transplant function gained more weight, suggesting a pivotal role of improved appetite on weight gain post transplantation. Most of the weight gain occurred during the first year.

A comparative study of caudal bupivacaine and midazolam-bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery.

OBJECTIVE: This study was designed to evaluate the analgesic efficacy of caudal midazolam-bupivacaine combination in providing post-operative pain relief in children undergoing genitourinary surgery and to study the occurrence of adverse effects. SUBJECTS AND METHODS: Thirty children, aged 2 to 8 years, scheduled for genitourinary surgery were allocated randomly to receive either 0.25% bupivacaine 0.5 ml/kg (group B; n = 15) or 0.25% bupivacaine 0.5 ml/kg with 50 microg/kg midazolam (group BM; n = 15) by the caudal route immediately after induction of general anesthesia. Heart rate, arterial blood pressure and oxygen saturation were monitored throughout the study period. Postoperative pain was assessed at regular intervals for 12 hours using an objective pain score. Analgesia was supplemented whenever the pain score was > or = 4. Duration of analgesia, as well as the requirement of additional analgesics, were noted. RESULTS: Lowest pain scores were observed with the addition of midazolam to caudal bupivacaine (p < 0.01). Duration of analgesia was longer in group BM (11 +/- 0.5 h) as compared to group B (7.4 +/- 2.1 hours) (p < 0.05). Fewer children (26.6%) required additional analgesia in the combination group whereas in group B, 60% of the children received analgesic supplements within 6 hours after surgery (p < 0.05). There were no significant changes in heart rate, blood pressure and oxygen saturation in both groups. We observed no untoward event in either of the groups. CONCLUSION: Caudal administration of bupivacaine-midazolam mixture prolongs post-operative analgesia compared to bupivacaine alone without causing any adverse effects.

Cardio-vascular effects of vecuronium & pancuronium in patients undergoing elective closed mitral valvotomy.

Vecuronium, a monoquaternary analogue of pancuronium, the neuromuscular blocker, was compared with pancuronium in 50 patients undergoing elective closed mitral valvotomy. The patients were randomly divided into two groups of 25 each, and the muscle relaxants were administered in a dose of 0.1 mg/kg body weight. Both the agents produced identical intubating conditions at 3 min. Vecuronium showed a significantly shorter onset of action, as compared to pancuronium. The latter significantly increased the heart rate throughout the period of study whereas vecuronium significantly decreased the heart rate, 25 min after administration. There was significant increase in the mean arterial pressure (MAP) at tracheal intubation in both the groups, which persisted throughout the period of study in pancuronium group. There was a significant fall in MAP at 30 min after relaxant in vecuronium group. The incidence of arrythmias was similar and significant in both the groups. Vecuronium, thus showed a quicker onset of action with minimal haemodynamic effects, as compared to pancuronium in patients undergoing closed mitral valvotomy.

Effect of varying doses of fentanyl with low dose spinal bupivacaine for caesarean delivery in patients with pregnancy-induced hypertension.

The purpose of this study was to evaluate haemodynamic stability, perioperative analgesia and neonatal outcome following intrathecal 0.5% bupivacaine 7.5 mg with varying doses of fentanyl, in parturients with pregnancy-induced hypertension. Forty-five parturients with pregnancy-induced hypertension scheduled for caesarean section were randomly allocated to receive 7.5 mg bupivacaine with saline 1 mL (group B), fentanyl 10 microg (group Bf10) or fentanyl 20 microg (group Bf20) intrathecally. Heart rate, blood pressure, and sensory block were recorded at regular intervals. Pain, nausea, vomiting, pruritus or any other side effects were sought. Neonatal outcome was assessed using Apgar score and umbilical artery blood gas analysis. Adequate surgical anaesthesia was established in all three groups. There was a statistically significant fall in mean arterial pressure in all three groups within 4-6 min of subarachnoid block (P<0.05), but the decrease in MAP was <20% of baseline in all three groups. Pain and discomfort during surgery were experienced more frequently in group B than in groups Bf10 and Bf20 (P<0.05). Duration of postoperative analgesia was significantly longer in group Bf20 (5.55+/-1.18 h) than in group Bf10 (3.97+/-2.12 h) and group B (3.27+/-1.8 h) (P<0.05). Neonatal outcome was similar in the three groups. Intrathecal fentanyl with low dose bupivacaine provides good surgical anaesthesia and prolongs the duration of analgesia without haemodynamic or neonatal compromise in patients with pregnancy-induced hypertension undergoing caesarean delivery.

Tetanus.

Tetanus is a potentially life threatening disease affecting nearly 50,000 to 1 million people world wide every year. Four major clinical forms of tetanus are described i.e. generalized, cephalic, localized and neonatal. Neonatal tetanus is particularly common in developing countries, due to unhygienic child birth practices, social taboos and improper immunization of pregnant mothers. Management of this disorder involves a team approach and aims at eradicating focus of infection, neutralizing the toxin, controlling spasms and dysautonomia and providing adequate ventilatory and supportive care. Metronidazole may be the preferred antibiotic although penicillin is still used frequently. Adequate wound debridement is necessary to prevent spore germination. Spasms are usually managed by sedatives like diazepam and neuromuscular blocking agents. Magnesium sulphate is an attractive substitute and may be tried if ventilatory facilities are unavailable. Use of baclofen is potentially advantageous but cannot be routinely prescribed. Dysautonomia is difficult to manage and requires therapy with benzodiazepines, morphine, magnesium sulphate, adrenergic blockers and recently tried baclofen therapy. Supportive care including ventilatory assistance are highly essential for successful outcome of the patients. It is imperative that complications are diagnosed early and managed appropriately. Immunization is extremely effective and is the key to prevention. Adequate steps and measures should be taken to increase awareness of this potentially preventable disease.

Peripheral neuropathy in tetanus : a clinical, neuroelectrophysiological and histological evaluation.

Nineteen patients (14 males and 5 females), who had tetanus were evaluated for polyneuropathy by clinical examination, neuroelectromyography and sural nerve biopsy. Three patients (16) had clinically evident distal symmetrical polyneuropathy. Therewas a significant prolongation of mean median motor distal latency (p<0.02) peroneal motor distal latency (p<0.001) and reduction of sural sensory nerve action potentials (p<0.001) in these patients in comparison to controls. Electromyographic sampling of tibialis anterior muscle revealed wide variation in motor unit action potential duration and amplitude. Denervation phenomena including fibrilations and positive sharp waves were present in 4 patients (21) and complex repetitive discharges were present in 9 patients (47.4). Sural nerve histology was performed in 9 patients. It revealed mild to moderate loss of myelinated fibres in 4 cases (44.4). There is evidence that in tetanus there is a distal predominantly sensory polyneuropathy.

Intracranial pressure changes with different doses of lignocaine under general anaesthesia.

The effect of intravenous lignocaine on intracranial pressure (ICP) was studied on thirty patients of either sex, aged above 5 years and scheduled for elective ventriculoperitoneal shunt surgery. The patients were randomly divided into 3 groups, which received intravenous lignocaine in the dose of 1 mg, 1.5 mg and 2 mg/kg body weight respectively. Intracranial pressure, heart rate, ECG, arterial pressure and arterial blood gases were monitored at various intervals for a period of 30 minutes. Maximum decrease in ICP was seen at 2 minutes after IV lignocaine in all the three groups (p<0. 001). The fall in ICP was significantly more in group II and group III (35.65% and 37.5% respectively) as compared to group I (17.47%) (p<0.001). This fall in ICP in all the three groups persisted below the basal level, throughout the study period. None of the groups showed any significant change in the heart rate, but a statistically significant fall in arterial pressure was observed in group III (p<0. 05). In conclusion intravenous lignocaine, in a dose of 1.5 mg/kg, causes significant fall in ICP without causing any untoward cardiovascular effects and is recommended for routine clinical use.

Efficacy of bupivacaine infiltration in preventing haemodynamic changes during craniotomy.

This study was carried out in sixty adult patients of either sex, to assess the efficacy of bupivacaine infiltration in different concentrations to prevent haemodynamic responses during craniotomy. The patients were randomly divided into 4 groups of15 each and scalp was infiltrated along the line of skin incision using either normal saline or 0.5, 0.25 or 0.125 bupivacaine. Patients were premedicated with morphine and promethazine and were anaestetised using conventional general anaesthesia technique including 02, N20 vecuronium and morphine. Ventilation was controlled so as to maintain PaCO2 between 25-30 mm Hg. EKG, heart rate and direct arterial pressure were monitored at various events during craniotomy. In control group there was a statistically significant increase in systolic arterial pressure and heart rate after scalp infiltration, scalp incision, during scalp flap reflection, burr hole formation, giglisaw operation and dural incision. In bupivacaine groups there was no significant alteration in arterial blood pressure or heart rate through out the period of study. On comparing the four groups it was observed that rise in arterial pressure and heart rate was significantly more in control group. Similarly a significantly more increasein systolic arterial pressure was observed in bupivacaine (0.125) group as compared to other trial groups. We recommend the haemodynamic changes during craniotomy.

Anaesthetic and intensive care aspects of spinal injury.

Over the last few years, spinal injuries have been classified depending upon their causative mechanism and on the basis of three column concept of the structure of vertebral column. The concept of primary and secondary injury has laid more stress on prevention and treatment of secondary injury. Methyl prednisolone still remains the drug of choice for prevention of secondary injury. Spinal injury involves all organ systems of the body depending on the level of lesion. Immobilisation of injured spine and maintenance of adequate airway after spinal injury need immediate attention. Orotracheal intubation under general anaesthesia, with manual in-line traction, is still considered the best method. Hypotension, hypertension and hyperglycaemia should be avoided during anaesthesia. Care should be taken to avoid effects of autonomic hyper reflexia. Spinal cord functions should be monitored and, if required, induced hypotension can be used with adequate monitoring.

Effect of intraperitoneal administration of sodium nitroprusside on the efficacy of peritoneal dialysis.

A prospective randomised trial of intraperitoneal sodium nitroprusside (SNP) administration on the efficacy of acute intermittent peritoneal dialysis was carried out in 40 adult patients of acute or acute on chronic renal failure. A total of 36 cycles of peritoneal dialysis (PD) with an exchange volume of 1 litre and duration of 1 hour per cycle were given to each patient. The 36 cycles of PD were divided into 12 clearance periods (I-XII) of 3 cycles each. SNP was added in a dosage of 4 mg/l of dialysate in clearance period II, IV, VI and VIII. Of 40 patients, 20 were subjected to standard PD (Gp A) while the other 20 received SNP added PD (Gp B). The peritoneal clearance of urea, creatinine, percentage fall of blood urea, serum creatinine and protein loss during the various clearance periods were compared in the two groups. It was observed that group B patients had significantly higher peritoneal clearance and the percentage reduction in the blood levels of urea and creatinine. Protein loss per clearance period was also significantly higher in group B patients. Twenty two cycles of SNP added PD were as effective as 36 cycles of standard PD. No systematic untoward effects of SNP were observed. It is therefore, concluded that intraperitoneal SNP administration is a safe and effective way of increasing the efficacy of PD thus reducing the duration of treatment.

Oculocardiac reflex during retinal surgery using peribulbar block and nitrous narcotic anesthesia.

BACKGROUND AND OBJECTIVES: This study was designed to examine the effects of local and general anesthesia on the oculocardiac reflex (OCR) in adults during retinal detachment surgery, with an aim of determining the safest type of anesthesia and on which extraocular muscle traction causes a higher incidence of OCR. PATIENTS AND METHODS: The study was performed on 30 American Society of Anesthesiologists-I patients (age range 40-60 years) who were undergoing retinal detachment surgery. Fifteen patients underwent surgery with general anesthesia and 15 were given a local peribulbar block. A fixed traction of 400 g was applied to all the extraocular muscles, and the heart rate, rhythm, and electrocardiogram of each patient was monitored. RESULTS: The overall incidence of OCR was higher with general anesthesia (63.3%) than with local anesthesia (14.4%). There was a significant decrease in heart rate for the rectus muscles (P < .0005) as well as the oblique muscles (P < .005) during traction with general anesthesia. All four rectus muscles were equally sensitive in eliciting the reflex. The incidence of dysrhythmias was 20% with general anesthesia and 6.67% with local anesthesia. CONCLUSION: This study showed that local anesthesia produces less bradycardia and ectopic arrhythmias and, therefore, may be safer and better than general anesthesia for surgeries in which traction of extraocular muscles is required.

Chest ultrasonography in emergency Cesarean delivery in multi-valvular heart disease with pulmonary edema during spinal anesthesia.

Valvular heart disease in a parturient presenting for Cesarean section is challenging. A 25 year old primigravida parturient with severe mitral stenosis, mild mitral regurgitation, mild aortic regurgitation, and mild pulmonary arterial hypertension required Cesarean delivery after developing pulmonary edema. Low-dose spinal with hyperbaric bupivacine 0.5% 1.8 mL plus 25 µg of fentanyl was used for anesthesia. Chest ultrasonography (US) and transthoracic echocardiography (TTE) were used for monitoring purposes. Spinal-induced preload reduction improved the pulmonary edema, as evidenced by chest US. Chest US and TTE helped in fluid management.

CSF p-Tau levels in the prediction of Alzheimer's disease.

The two hallmarks of Alzheimer's disease (AD) are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are formed due to the hyperphosphorylation of tau protein. There is an urgent need to develop a reliable biomarker for the diagnosis of AD. Cerebrospinal fluid (CSF) is surrounding the brain and reflects the major neuropathological features in the AD brain. Diagnosis, disease progression and drug actions rely on the AD biomarkers. Mainly CSF tau and phosphorylated tau (p-Tau) have been observed to serve the purpose for early AD. Keeping in view the early appearance of p-Tau in CSF, we analyzed p-Tau levels in 23 AD, 23 Non AD type dementia (NAD), 23 Neurological control (NC) and 23 Healthy control (HC) North Indian patients. The levels of p-Tau were found to be increased in AD patients (67.87±18.05 pg/ml, SEM 3.76) compared with NAD (47.55±7.85 pg/ml, SEM 1.64), NC (34.42±4.51 pg/ml, SEM 0.94) and HC (27.09±7.18 pg/ml, SEM 1.50). The resulting sensitivity for AD with NAD was 80.27% whereas with respect to the NAD, NC and HC was 85.40%. Therefore elevated levels of p-Tau in AD can be exploited as a predictive biomarker in North Indian AD patients.

Cerebrospinal fluid profile of amyloid ß42 (Aß42), hTau and ubiquitin in North Indian Alzheimer's disease patients.

Alzheimer's disease (AD) is the most common form of dementia, and is characterized by the degeneration of neurons and their synapses, and a higher number of amyloid plaques and neurofibrillary tangles (NFTs) compared with that found in non-demented individuals. Amyloid-ß-peptides (Aß) are major components of amyloid plaques in AD brain whereas NFTs are composed of Tau and associated with ubiquitin. The aim of the present study was to analyze the levels of Aß42, hTau (total Tau) and ubiquitin in CSF of North Indian population. CSF Aß42, Tau and ubiquitin were measured in CSF of AD patients as well as controls using ELISA assays. Here we report low Aß42 levels in AD patients (324.24±76.38pg/ml) as compared to those in non-AD (NAD) (668.34±43.13pg/ml), neurological controls (NCs) (727.28±46.49pg/ml) and healthy controls (HCs) (976.47±124.46pg/ml). In contrast, hTau and ubiquitin levels were significantly high (568.65±48.89pg/ml and 36.82±4.34ng/ml, respectively) in AD patients compared to those in NAD, NC and HC. The hTau levels were 267.37±36.64pg/ml, 167.34±44.27pg/ml and 107.62±24.27pg/ml in NAD, NC and HC, respectively. Similarly, ubiquitin levels were 23.57±2.32ng/ml, 19.76±3.64ng/ml and 13.24±4.56ng/ml in NAD, NC and HC, respectively. In conclusion, low Aß42 and high Tau-ubiquitin levels were found in North Indian AD patients.

Apo-Eε4 allele in conjunction with Aß42 and tau in CSF: biomarker for Alzheimer's disease.

The objective of this study was to elucidate an association between Apo- Eε4 allele and CSF biomarkers Aß42 and tau for the diagnosis of Alzheimer's Disease (AD) patients. Aß42 and tau protein concentrations in CSF were measured by using ELISA assays. The levels of Aß42 were found to be decreased where as tau levels increased in AD patients. Moreover in AD patients Apo-Eε4 allele carriers have shown low Aß42 levels (328.86 ± 99.0 pg/ml) compared to Apo-Eε4 allele non-carriers (367.52 ± 5 7.37 pg/ml), while tau levels were higher in Apo-Eε4 allele carriers (511 ± 44.67 pg/ml) compared to Apo-Eε4 allele non-carriers (503.75 ± 41.08 pg/ml). Combination of Aß42 and tau resulted in sensitivity of 75.38% and specificity of 94.82% and diagnostic accuracy of 84.30% for AD compared with the controls. Therefore low Aß42 and elevated tau concentrations in CSF may prove to be a better diagnostic marker for AD along with the Apo-Eε4 allele.