Short-course radiotherapy with consolidation chemotherapy versus conventionally fractionated long-course chemoradiotherapy for locally advanced rectal cancer: randomized clinical trial.

BACKGROUND: The trial hypothesis was that, in a resource-constrained situation, short-course radiotherapy would improve treatment compliance compared with conventional chemoradiotherapy for locally advanced rectal cancer, without compromising oncological outcomes. METHODS: In this open-label RCT, patients with cT3, cT4 or node-positive non-metastatic rectal cancer were allocated randomly to 5 × 5 Gy radiotherapy and two cycles of XELOX (arm A) or chemoradiotherapy with concurrent capecitabine (arm B), followed by total mesorectal excision in both arms. All patients received a further six cycles of adjuvant chemotherapy with the XELOX regimen. The primary endpoint was treatment compliance, defined as the ability to complete planned treatment, including neoadjuvant radiochemotherapy, surgery, and adjuvant chemotherapy to a dose of six cycles. RESULTS: Of 162 allocated patients, 140 were eligible for analysis: 69 in arm A and 71 in arm B. Compliance with planned treatment (primary endpoint) was greater in arm A (63 versus 41 per cent; P = 0.005). The incidence of acute toxicities of neoadjuvant therapy was similar (haematological: 28 versus 32 per cent, P = 0.533; gastrointestinal: 14 versus 21 per cent, P = 0.305; grade III-IV: 2 versus 4 per cent, P = 1.000). Delays in radiotherapy were less common in arm A (9 versus 45 per cent; P < 0.001), and overall times for completion of neoadjuvant treatment were shorter (P < 0.001). The rates of R0 resection (87 versus 90 per cent; P = 0.554), sphincter preservation (32 versus 35 per cent; P = 0.708), pathological complete response (12 versus 10 per cent; P = 0.740), and overall tumour downstaging (75 versus 75 per cent; P = 0.920) were similar. Downstaging of the primary tumour (ypT) was more common in arm A (P = 0.044). There was no difference in postoperative complications between trial arms (P = 0.838). CONCLUSION: Reduced treatment delays and a higher rate of compliance were observed with treatment for short-course radiotherapy with consolidation chemotherapy, with no difference in early oncological surgical outcomes. In time- and resource-constrained rectal cancer units in developing countries, short-course radiotherapy should be the standard of care.

Self-assembly of colloidal magnetic particles: energy landscapes and structural transitions.

The self-assembly of colloidal magnetic particles is of particular interest for the rich variety of structures it produces and the potential for these systems to be reconfigurable. In the present study we characterised the structures for clusters of N spherical colloidal magnetic particles in the presence of short-ranged attractive depletion interactions up to N = 50. The morphologies that we observed include linear chains, circular rings, stacks of two and three circular rings, as well as compact structures consisting of sheets. For size-selected clusters we illustrate the organisation of the low-lying part of the potential energy landscape, and analyse pathways for the structural transitions of interest, including the effect of an external static magnetic field.

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma.

BACKGROUND: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). RESULTS: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. CONCLUSIONS: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01210495.

Ergonomic basket design to reduce cumulative trauma disorders in tea leaf plucking operation.

Work related musculoskeletal disorders are seen as an indicating parameter of occupational stress among the women workers engaged in tea leaf plucking operation. The hand plucking (no mechanized plucking is practiced in Assam) being a highly repetitive task requires forceful exertions to reach to the distant periphery of the tea bushes and mechanical compression (pressing against hard surfaces). Specifically it aggravates with awkward positions adopted. The current research addresses to minimize the risk factors associated with CTDs and to ascertain the role of ergonomic design development in improving the situation. Women workforce engaged in tea industry in Assam suffer from back, shoulder, arm and finger pains. Workers perform the activity for 440 minutes in the entire shift with one hour lunch break in between in the garden itself. An ergonomic investigation aiming at studying the strain index of plucking operation in tea industry was conducted. While performing the operation workers were found to assume unnatural posture which is static as well as highly dynamic with a load (tea leaf collecting basket up to weight of 30 kg when filled with plucked leaves) at back. With gradual increment of load and pain though the load is released intermittently the strain level found to remain at a high level. The total QEC scores found for plucking activity was 110 out of 138. To improve the situation and to reduce the work related upper limb disorder (WRULD) an ergonomically designed basket was conceived and trial results showed improvements. The newly designed plucking basket fits the back curvature of the workers well, which keeps the basket in place unlike the existing round basket. The new basket is light in weight having more leaf capacity. Significant reduction in energy expenditure and MSDs suffered was observed while using improved basket over existing basket.

Lean thinking: can it improve the outcome of fracture neck of femur patients in a district general hospital?

We present our experience in the management of hip fracture patients after the application of a value-stream approach, the Lean framework, in our trust. This system uses available resources in an efficient manner whilst eliminating waste. A statistically significant reduction of 5% and 9.3% was noted in the 30-day and overall mortality, respectively, after implementing 'Lean thinking'. Further improvements were also noted in door-to-theatre time, use of trauma beds and early discharge from hospitals. To our knowledge, this is the largest study in the literature where the Lean framework has been successfully employed for the management of a very challenging health-care issue faced by the National Health Service. Future prospective studies are, however, needed to reconfirm these results and to evaluate the components that are most critical to the success of the implemented framework.

Primary synovial osteochondromatosis of the first metatarsophalangeal joint, literature review of a rare presentation and a case report.

Synovial osteochondromatosis is a rare condition, found mainly in larger joints, where as it is particularly rarer in small joints especially the metatarsophalangeal joint. We report the case of a 45-year-old man with primary synovial osteochondromatosis in the first metatarsophalangeal joint. Following surgical intervention, the diagnosis was confirmed with histological examination. The patient had successful management and is completely symptom free on 12-month review. A summary of the case and review of the current literature with the incidence of this condition and risks involved are discussed.

Spectrum of renal disorders in a tertiary care hospital in Haryana.

INTRODUCTION: There is a paucity of data pertaining to spectrum of renal diseases in various parts of India. Available literature has emphasized more on specific clinical syndromes of renal diseases rather than over all spectrum. The present study highlights specimen of symptomatic renal disorders at a tertiary care hospital in Haryana and will find place for better resource management and planning. MATERIALS AND METHODS: It included 1806 patients either presenting for the first time to nephrology outpatient department of admitted between Jan 1996 - Dec 2001 to the institute. The study was retrospective for five years (1996-2000) and prospective for one year. Records of all these patients were analyzed and patients were grouped in different renal syndromes. RESULTS: Mean age of patients was (38.79 +/- 15.15 years) with male preponderance in all renal syndromes. Chronic renal failure (CRF) was the commonest presentation (56.02%). Nephrotic syndrome accounted for 22.36% whereas acute renal failure (ARF) was seen in 12.84%. Other presentations were acute nephritic syndrome (6.75%) and asymptomatic urinary abnormality (AUA) (0.99%). Chronic glomerulonephritis (CGN) (39.32%) and diabetic nephropathy (DN) (19.16%) were leading causes of CRF. Medical ARF accounted for 2/3rd of the cases of ARF and surgical etiology was seen in 1/5th of causes whereas obstetric cause was responsible for 1/7th of the cases. Minimal change disease (MCD) (33.33%) was the commonest cause of primary nephrotic syndrome followed by membranoproliferative glomeruolonephritis (MPGN). Secondary glomerular diseases were found in 21.28%. Post-streptococcal glomerulonephritis (PSGN) was the commonest cause of nephritic syndrome (37.70%). CONCLUSION: It is the first large study of its kind from a tertiary health care centre of Haryana. Male patients in their peak of life (3rd and 4th decade) were the major candidates requiring renal care with CRF as the commonest presentation and diabetic nephropathy as the second commonest cause of CRF after CGN. We need more Indian studies on spectrum of renal diseases for better available resource management.

Organophosphate induced delayed neuropathy.

A 19 year young male who consumed organophosphorous compound and required assisted mechanical ventilation for two weeks, later on developed delayed neuropathy is described.

Characterization of an eukaryotic peptide deformylase from Plasmodium falciparum.

Ribosomal protein synthesis in eubacteria and eukaryotic organelles initiates with an N-formylmethionyl-tRNA(i), resulting in N-terminal formylation of all nascent polypeptides. Peptide deformylase (PDF) catalyzes the subsequent removal of the N-terminal formyl group from the majority of bacterial proteins. Until recently, PDF has been thought as an enzyme unique to the bacterial kingdom. Searches of the genomic DNA databases identified several genes that encode proteins of high sequence homology to bacterial PDF from eukaryotic organisms. The cDNA encoding Plasmodium falciparum PDF (PfPDF) has been cloned and overexpressed in Escherichia coli. The recombinant protein is catalytically active in deformylating N-formylated peptides, shares many of the properties of bacterial PDF, and is inhibited by specific PDF inhibitors. Western blot analysis indicated expression of mature PfPDF in trophozoite, schizont, and segmenter stages of intraerythrocytic development. These results provide strong evidence that a functional PDF is present in P. falciparum. In addition, PDF inhibitors inhibited the growth of P. falciparum in the intraerythrocytic culture.

Characterization of a novel serine/threonine protein phosphatase (PfPPJ) from the malaria parasite, Plasmodium falciparum.

A novel protein phosphatase cDNA of the PPP superfamily was identified from the malaria parasite, Plasmodium falciparum (Pf), and tentatively named PfPPJ. The predicted primary structure of the phosphatase contained all the known conserved motifs of the PPP superfamily essential for catalytic activity. The enzyme was specific for dephosphorylation of phosphoserine and phosphothreonine residues with very little activity against phosphotyrosine residues. However, the sequence at its C-terminal end was unique, and was consistent with its resistance to the classical PP2A-specific inhibitors such as okadaic acid and microcystin-LR, and the PP1-specific inhibitor, mammalian heat-stable inhibitor-2 (I-2). Even the catalytic core of PfPPJ had a sequence substantially different from the other PPPs such that PfPPJ could be placed in an apparently separate phylogenetic branch. At 294 amino acids residues, PfPPJ was one of the smallest okadaic acid-resistant PPP phosphatases known. By Northern blot analysis, the expression of the PfPPJ mRNA showed the following pattern: schizont > ring > trophozoite, which closely paralleled the expression of the protein, as determined by immunofluorescence. Together, these results suggested a parasitic stage-specific transcriptional regulation of this novel and potentially unique protozoan phosphatase.

Co-ordinated programme of gene expression during asexual intraerythrocytic development of the human malaria parasite Plasmodium falciparum revealed by microarray analysis.

Plasmodium falciparum is a protozoan parasite responsible for the most severe forms of human malaria. All the clinical symptoms and pathological changes seen during human infection are caused by the asexual blood stages of Plasmodium. Within host red blood cells, the parasite undergoes enormous developmental changes during its maturation. In order to analyse the expression of genes during intraerythrocytic development, DNA microarrays were constructed and probed with stage-specific cDNA. Developmental upregulation of specific mRNAs was found to cluster into functional groups and revealed a co-ordinated programme of gene expression. Those involved in protein synthesis (ribosomal proteins, translation factors) peaked early in development, followed by those involved in metabolism, most dramatically glycolysis genes. Adhesion/invasion genes were turned on later in the maturation process. At the end of intraerythrocytic development (late schizogony), there was a general shut-off of gene expression, although a small set of genes, including a number of protein kinases, were turned on at this stage. Nearly all genes showed some regulation over the course of development. A handful of genes remained constant and should be useful for normalizing mRNA levels between stages. These data will facilitate functional analysis of the P. falciparum genome and will help to identify genes with a critical role in parasite progression and multiplication in the human host.

PfPK6, a novel cyclin-dependent kinase/mitogen-activated protein kinase-related protein kinase from Plasmodium falciparum.

We have isolated a novel protein kinase cDNA, PfPK6, by differential display RT-PCR (DDRT-PCR) of mRNA obtained from different asexual erythrocytic stages of Plasmodium falciparum, which shows sequence similarity to both cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) family members. The 915 bp open reading frame (ORF) is interrupted by seven introns and encodes a 305-residue polypeptide with a predicted molecular mass of 35848 Da. Several cDNA clones with some of the intron sequences were isolated, indicating alternate or defective splicing of PfPK6 transcripts because the gene seems to be a single copy located on chromosome 13. The similarity of the catalytic domain of PfPK6 to those of CDK2 and MAPK is 57.3% and 49.6%, respectively. The signature PSTAIRE (single-letter amino acid codes) CDK motif is changed to SKCILRE in PfPK6. The TXY residues that are phosphorylated in MAPKs for their activation are T(173)PT in PfPK6. Three size classes of PfPK6 transcripts of 6.5, 2.0 and 1.1 kb are up-regulated during the transition of P. falciparum from ring to trophozoite. Western blot analysis suggested the expression of a 35 kDa polypeptide in trophozoites and schizonts. Immunofluorescence studies indicated both nuclear and cytoplasmic localization of PfPK6 in trophozoite, schizont and segmenter stages. In vitro, recombinant PfPK6 phosphorylated itself and also exogenous substrates, histone and the small subunit of the malarial ribonucleotide reductase (R2). The kinase activity of PfPK6 is sensitive to CDK inhibitors such as olomoucine and roscovitine. PfPK6 showed a preference for Mn(2+) over Mg(2+) ions as a cofactor. The Lys(38)-->Arg mutant is severely defective in its interaction with ATP and bivalent cations and somewhat defective in catalytic rate for R2 phosphorylation.

The cell cycle in protozoan parasites.

Research into cell cycle control in protozoan parasites, which are responsible for major public health problems in the developing world, has been hampered by the difficulties in performing classical genetic analysis with these organisms. Nevertheless, in a large part thanks to the data gathered in other eukaryotic systems and to the acquisition of the sequences of parasite genes homologous to cell cycle regulators, many molecular tools required for an in-depth study of the cell cycle in protozoan parasites have been collected over the past few years. Despite the considerable phylogenetic divergence between these organisms and other eukaryotes, and notwithstanding important specificities such as the apparent lack of checkpoints during cell cycle progression, available data indicate that the major families of cell cycle regulators appear to operate in protozoan parasites. Functional studies are now needed to define the precise role of these regulators in the life cycle of the parasites, and to possibly validate cell cycle control elements as potential targets for chemotherapy.