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Biomedical subjects

P Khandelwal

Publications and source records attributed to P Khandelwal.

16 recordsLinked to original sources
PubMed2005

Treatment of ruptured intracranial aneurysms: our approach.

OBJECTIVE: Subarachnoid hemorrhage (SAH) often results in devastating neurological deficits requiring hospitalization and loss of independence. This is often a difficult time for patients and their families who are struggling to cope with this sudden illness. Current treatment options include surgical clipping of the aneurysm or endovascular obliteration using Guglielmi detachable coils. Our purpose in writing this paper was to review the factors that determine the choice of treatment. In addition to this we wanted to study the benefits of surgical clipping for ruptured aneurysms over endovascular coiling. MATERIAL AND METHODS: We studied--retrospectively--450 cases of ruptured cerebral aneurysms admitted to our institution from 1997 to 2003. Out of these, 324 were subjected to surgical clipping and 126 to endovascular techniques. The outcome was studied using the Glasgow Outcome Score (GOS). RESULTS: Of the 324 cases of surgical clipping 222 had a good recovery, 38 had moderate disability, 15 had severe disability, 13 became vegetative and 36 patients died. In the endovascular group 34 had a good recovery, 22 had moderate disability, 18 had severe disability, 15 became vegetative and 37 patients died. Grade to Outcome was compared for both forms of treatment. In our series clipping for ruptured aneurysm was preferred to coiling in fusiform-shaped aneurysms, large or giant aneurysms, MCA aneurysms, blister aneurysms, complex configurations, partially thrombosed aneurysms and aneurysms associated with cerebral hemorrhage. Coiling was performed for basilar tip and trunk aneurysms, high anterior communicating artery aneurysms, patients in subacute stages of subarachnoid hemorrhage, and those with associated medical complications. CONCLUSION: Based on this study we were able to formulate a few definite indications for clipping, even in the times of advanced endovascular techniques. In addition we could also prove the benefits of surgical clipping over the endovascular technique in severe subarachnoid hemorrhage.

Aneurysm, Ruptured↗
PubMed2003

A phase II multicenter study of combined topotecan and gemcitabine as first line chemotherapy for advanced non-small cell lung cancer.

UNLABELLED: This trial was designed to determine the 1-year survival rate, efficacy, and safety, produced by topotecan and gemcitabine as first line chemotherapy in advanced non-small cell lung cancer (ANSCLC). Fifty-three patients were enrolled; 51 received treatment. Topotecan 1 mg/m(2), days 1-5 and gemcitabine 1 g/m(2) days 1 and 15 were administered IV, each drug over 30 min; cycles consisted of 28 days. Treatment continued until progressive disease or intolerable toxicity. Nineteen patients (36%) had Eastern Cooperative Oncology Group criteria performance status (ECOG PS) = 0, 34 (64%) PS = 1. Median age was 64 years; 37 patients (70%) were male. HISTOLOGY: adenocarcinoma (42%), squamous cell carcinoma (28%), large cell (19%), and unclassified (11%). Among 47 evaluable patients, eight (17%) had partial response, 11 (23%) had stable disease. One-year survival was 39% and median survival was 7.6 months (range, < 1-19.6). Grade 3 and 4 toxicities included neutropenia (53%), anemia (18%), thrombocytopenia (12%), asthenia (8%), and gastrointestinal disorders (8%); three patients (6%) experienced neutropenic fever. There were no treatment-related deaths. The combination topotecan/gemcitabine produced a 1-year survival similar to previous platinum-based regimens, when used as first line chemotherapy for ANSCLC. The toxicity profile was acceptable.

Adenocarcinoma↗
PubMed2001

Fine particle (PM2.5) personal exposure levels in transport microenvironments, London, UK.

In order to investigate a specific area of short-term, non-occupational, human exposure to fine particulate air pollution, measurements of personal exposure to PM2.5 in transport microenvironments were taken in two separate field studies in central London, UK. A high flow gravimetric personal sampling system was used; operating at 16 l min(-1); the sampler thus allowed for sufficient sample mass collection for accurate gravimetric analysis of short-term travel exposure levels over typical single commute times. In total, samples were taken on 465 journeys and 61 volunteers participated. In a multi-transport mode study, carried out over 3-week periods in the winter and in the summer, exposure levels were assessed along three fixed routes at peak and off-peak times of the day. Geometric means of personal exposure levels were 34.5 microg m(-3) (G.S.D.= 1.7, n(s) = 40), 39.0 microg m(-3) (G.S.D. = 1.8, n(s) = 36), 37.7 microg m(-3) (G.S.D. = 1.5, n(s) = 42), and 247.2 microg m(-3) (G.S.D. = 1.3, n(s) = 44) for bicycle, bus, car and Tube (underground rail system) modes, respectively, in the July 1999 (summer) measurement campaign. Corresponding levels in the February 2000 (winter) measurement campaign were 23.5 microg m(-3) (G.S.D. = 1.8, n(s) = 56), 38.9 microg m(-3) (G.S.D. = 2.1, n(s) = 32), 33.7 microg m(-3) (G.S.D. = 2.4, n(s) = 12), and 157.3 microg m(-3) (G.S.D. = 3.3, n(s) = 12), respectively. In a second study, exposure levels were measured for a group of 24 commuters travelling by bicycle, during August 1999, in order to assess how representative the fixed route studies were to a larger commuter population. The geometric mean exposure level was 34.2 microg m(-3) (G.S.D. = 1.9, n(s) = 105). In the fixed-route study, the cyclists had the lowest exposure levels, bus and car were slightly higher, while mean exposure levels on the London Underground rail system were 3-8 times higher than the surface transport modes. There was significant between-route variation, most notably between the central route and the other routes. The fixed-route study exposure was similar in level and in variability to the 'real' commuters study, suggesting that the routes chosen and the number of samples taken provided a reasonably good estimate of the personal exposure levels in the transport microenvironments of Central London. This first comprehensive PM2.5 multi-mode transport user exposure assessment study in the UK also showed that mean personal exposure levels in road transport modes were approximately double that of the PM2.5 concentration at an urban background fixed site monitor.

Adult↗
PubMed2001

Spectroscopic evidence for the localization of Skyrmions near nu = 1 as T --> 0.

Optically pumped nuclear magnetic resonance measurements of 71Ga spectra were carried out in an n-doped GaAs/Al(0.1)Ga0.9As multiple quantum well sample near the integer quantum Hall ground state nu = 1. As the temperature is lowered (down to T approximately 0.3 K), a "tilted plateau" emerges in the Knight shift data, which is a novel experimental signature of quasiparticle localization. The dependence of the spectra on both T and nu suggests that the localization is a collective process. The frozen limit spectra appear to rule out a 2D lattice of conventional Skyrmions.

Journal Article↗
PubMed2001

Solution structure and dynamics of GCN4 cognate DNA: NMR investigations.

A 12 bp long GCN4-binding, self-complementary duplex DNA d(CATGACGTCATG)(2) has been investigated by NMR spectroscopy to study the structure and dynamics of the molecule in aqueous solution. The NMR structure of the DNA obtained using simulated annealing and iterative relaxation matrix calculations compares quite closely with the X-ray structure of ATF/CREB DNA in complex with GCN4 protein (DNA-binding domain). The DNA is also seen to be curved in the free state and this has a significant bearing on recognition by the protein. The dynamic characteristics of the molecule have been studied by (13)C relaxation measurements at natural abundance. A correlation has been observed between sequence-dependent dynamics and recognition by GCN4 protein.

Crystallography, X-Ray↗
PubMed2001

Structure of the type III secretion and substrate-binding domain of Yersinia YopH phosphatase.

Pathogenic strains of Yersinia deploy a type III secretion system to inject the potent tyrosine phosphatase YopH into host cells, where it dephosphorylates focal adhesion-associated substrates. The amino-terminal, non-catalytic domain of YopH is bifunctional; it is essential for the secretion and binding of the specific chaperone SycH, but also targets the catalytic domain to substrates in the infected cell. We describe the 2.2 A resolution crystal structure of residues 1-129 of YopH from Yersinia pseudotuberculosis. The amino-terminal alpha-helix (2-17), comprising the secretion signal, and beta-strand (24-28) of one molecule exchange with another molecule to form a domain-swapped dimer. Nuclear magnetic resonance (NMR) and gel filtration experiments demonstrated that YopH(1-129) could exist as a monomer and/or a dimer in solution. The topology of the dimer and the dynamics of a monomeric form in solution observed by NMR imply that YopH has the propensity to unfold partially. The dimer is probably not important physiologically, but may mimic how SycH binds to the exposed non-polar surfaces of a partially unfolded YopH. Phosphopeptide-induced perturbations in NMR chemical shifts define a substrate-binding surface on YopH(1-129) that includes residues previously shown by mutagenesis to be essential for YopH function.

Amino Acid Sequence↗
PubMed2000

Step-wise formation of helical structure and side-chain packing in a peptide from scorpion neurotoxin support hierarchic model of protein folding.

The mechanism of protein folding has been the subject of extensive investigation during the last decade, both because of its academic challenge and because of its relation to many diseases which are known to occur due to misfolding of proteins. In this context, we report here a systematic investigation on the step-wise formation of a helical structure by the addition of hexafluoroacetone, in a 14-residue peptide derived from a part of the scorpion neurotoxin protein. The NMR and circular dichroism results indicate that the peptide has an inherent propensity for helix formation and this is limited to the internal few residues in aqueous solution. With the addition of the fluorosolvent, the helical content progressively increases and spans the whole sequence. This is accompanied by concomitant packing of the side chains. These results provide support to the so-called hierarchic model of protein folding which dictates that the local sequence determines the secondary structures in the protein and the side chains play an important role in this process.

Acetone↗
PubMed2000

Compound radiofrequency-driven recoupling pulse sequences for efficient magnetization transfer by homonuclear dipolar interaction under magic-angle spinning conditions

The maximum of the transferred magnetization in rotating powdered solids under the radiofrequency-driven recoupling (RFDR) pulse sequence is enhanced by reducing the orientation dependence of the effective recoupled homonuclear dipolar interaction. The compound RFDR (CRFDR) pulse sequence for this enhancement consists of RFDR pulse units (tau(i)-pi-tau(R)-pi-1171;tau(i)) with different tau(i), where tau(R) is the sample rotation period, tau(i) and 1171;tau(i) (=tau(R) - tau(i)) are delays, and pi is a 180 degrees pulse. The delay tau(i) modifies the zero-quantum spin operators and the sample rotation-angle dependence of the recoupled dipolar Hamiltonian. The CRFDR pulse sequences were optimized for mixing by varying tau(i). Numerical simulation for the two-spin system only with a dipolar interaction and isotropic chemical shifts indicates that the transfer efficiency of CRFDR averaged over the powder is about 70%, which is 30% higher than the efficiency of the RFDR pulse over a broad range of about 1/tau(R) in resonance frequency difference. The CRFDR sequences need about 60% longer mixing times to maximize the transferred magnetizaion in comparison with the original RFDR sequence. Chemical shift anisotropy, the other dipolar interactions, and relaxation generally reduce the enhancement by CRFDR. Experiments for fully (13)C-labeled alanine, however, show that the maximum of the magnetization transferred with CRFDR from the carboxyl to alpha carbon is about 15% greater than that with RFDR. Copyright 2000 Academic Press.

Journal Article↗
PubMed1999

CD and NMR investigations on trifluoroethanol-induced step-wise folding of helical segment from scorpion neurotoxin.

A 14 amino acid residue peptide from the helical region of Scorpion neurotoxin has been structurally characterized using CD and NMR spectroscopy in different solvent conditions. 2,2,2-Trifluoroethanol (TFE) titration has been carried out in 11 steps from 0 to 90% TFE and the gradual stabilization of the conformation to form predominantly alpha-helix covering all of the 14 residues has been studied by 1H and 13C NMR spectroscopy. Detailed information such as coupling constants, chemical shift indices, NOESY peak intensities and amide proton temperature coefficients at each TFE concentration has been extracted and analysed to derive the step-wise preferential stabilization of the helical segments along the length of the peptide. It was found that there is a finite amount of the helical conformation in the middle residues 5-11 even at low TFE concentrations. It was also observed that > 75% TFE (v/v) is required for the propagation of the helix to the N and C termini and for correct packing of the side chains of all of the residues. These observations are significant to understanding the folding of this segment in the protein and may throw light on the inherent preferences and side chain interactions in the formation of the helix in the peptide.

Circular Dichroism↗
PubMed1999

Randomized, double-blind, placebo-controlled trial to evaluate the hematopoietic growth factor PIXY321 after moderate-dose fluorouracil, doxorubicin, and cyclophosphamide in stage II and III breast cancer.

PURPOSE: To measure the effect of PIXY321 (granulocyte-macrophage colony-stimulating factor/interleukin-3 S. cerevisiae fusion protein) on the incidence, duration, and complications of neutropenia and thrombocytopenia after moderate-dose fluorouracil 600 mg/m(2), doxorubicin 60 mg/m(2), and cyclophosphamide 750 mg/m(2) (FAC) chemotherapy in patients with stage II and III breast cancer. PATIENTS AND METHODS: In this multicenter, randomized, double-blind placebo-controlled trial, 71 women were to receive four 21-day cycles of treatment with moderate-dose FAC chemotherapy by short intravenous infusion on day 1, followed by either placebo or PIXY321 (375 microg/m(2) subcutaneously twice a day) on days 3 to 15. All patients were to receive prophylactic oral ciprofloxacin when the absolute neutrophil count was less than 1,000/microL. RESULTS: PIXY321 significantly reduced the incidence and duration of grade 3 and grade 4 neutropenia in cycles 1 and 2 and the duration of grade 3 neutropenia in cycles 1 through 4. In cycles 3 and 4, grade 3 thrombocytopenia was significantly more common with PIXY321 (P <.05). Two patients, both in the PIXY321 group, required platelet transfusions. Fever and hospitalization for intravenous antibiotics were significantly more common in the PIXY321 group during cycle 1 only. More patients in the PIXY321 group achieved hematologic recovery by day 22 in cycles 1 through 3, and time to recovery was significantly shorter with PIXY321 in all cycles. FAC dose intensity was roughly 2% higher in the PIXY321 group (P = NS). Nonhematologic events of any intensity occurring with significantly greater overall frequency in the PIXY321 group included injection-site reactions, fever, chills, abdominal pain, and arthralgia. No patient died on study or within 30 days of her last dose of study drug. CONCLUSION: PIXY321 decreased the incidence and duration of FAC-induced grade 3 and 4 neutropenia in cycles 1 and 2 and significantly shortened the time to hematologic recovery in all cycles. However, it produced more systemic toxicity as well as thrombocytopenia in cycles 3 and 4.

Adenocarcinoma↗
PubMed1999

Alpha-difluoromethylornithine as treatment for metastatic breast cancer patients.

DFMO (alpha-difluoromethylornithine) is an oral irreversible inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis. DFMO has been shown to have antiproliferative effects against several human cancers, and some studies have suggested that DFMO may have pro-apoptotic and anti-invasive properties as well. DFMO is well tolerated with minimal toxicity but has been associated with ototoxicity with prolonged daily administration. We conducted a Phase I/II tolerability, pharmacokinetic, and efficacy study of high-dose DFMO in metastatic breast cancer patients. Twenty-one patients were treated with 4800 mg of DFMO p.o. three times a day for 14 days, followed by a 2-week drug holiday on a 28-day cycle. Urinary polyamine and blood DFMO levels were measured at multiple time points during therapy. High-dose DFMO was well tolerated, and no clinically significant ototoxicity was noted. No patient achieved an objective antitumor response; however, one patient with heavily pretreated liver metastases has achieved stable disease for 18 months to date on DFMO. Putrescine, spermine, and spermidine urinary levels were suppressed with DFMO treatment and remained low during the 2-week drug holiday. High-dose DFMO on a schedule of 2 weeks on treatment followed by 2 weeks off is well tolerated, is not associated with ototoxicity, and leads to sustained suppression of urinary polyamine levels. Although not an active cytotoxic agent for metastatic breast cancer, the intriguing prolonged growth arrest of liver metastases in one patient highlights the potential clinical growth inhibitory properties of DFMO. We believe that DFMO is worthy of study as adjuvant therapy in primary breast cancer patients and as a chemopreventive agent.

Adult↗
PubMed1998

Ultraslow electron spin dynamics in GaAs quantum wells probed by optically pumped NMR

Optically pumped nuclear magnetic resonance (OPNMR) measurements were performed in two different electron-doped multiple quantum well samples near the fractional quantum Hall effect ground state nu = 13. Below 0.5 kelvin, the spectra provide evidence that spin-reversed charged excitations of the nu = 13 ground state are localized over the NMR time scale of about 40 microseconds. Furthermore, by varying NMR pulse parameters, the electron spin temperature (as measured by the Knight shift) could be driven above the lattice temperature, which shows that the value of the electron spin-lattice relaxation time tau1s is between 100 microseconds and 500 milliseconds at nu = 13.

Journal Article↗