Single-stage immediate breast reconstruction with acellular dermal matrix: Experience gained and lessons learnt from patient reported outcome measures.

INTRODUCTION: Acellular Dermal Matrix (ADM) assisted breast reconstruction has transformed the single-stage Immediate Breast Reconstruction (IBR) with an impact on the cosmetic outcomes. However, there is limited data available on patient reported outcomes. This study highlights the Patient Reported Outcome Measures (PROMs), post-operative complications and lessons learnt from ADM assisted single-stage immediate breast reconstruction. METHODS: This prospective study enrolled consecutive patients from Feb 2012 - May 2015 undergoing mastectomy with direct-to-implant ADM assisted breast reconstruction, using Strattice™ (Acelity, San Antonio, TX, USA). Patients were recruited from the beginning of our unit's use of ADMs and completed a post-operative questionnaire at 6 weeks, covering pre-operative, operative and post-operative outcomes. Information on tumour biology and post-operative complications was obtained from the medical notes. RESULTS: This study included 49 patients undergoing a total of 53 procedures. Following surgery 93.3% of women reported a high level of body confidence when clothed. 6.7% of patients reported severe post-operative pain during the first week. Mean length of hospital stay was 1.7 days, return to light activities was within 2.5 weeks and normal activities in 5.4 weeks. Implant loss at 3 months occurred in 5.7% of procedures, of which two thirds were smokers. CONCLUSIONS: PROMs for Strattice™ ADM based reconstruction show high levels of satisfaction with cosmetic outcomes, low incidences of severe post-operative pain and a short recovery process. PROMs help us to better describe patients' experience, allowing women to make more informed choices about ADM based breast reconstruction, which reassures and helps to achieve better outcomes.

The Rodin-Ohno hypothesis that two enzyme superfamilies descended from one ancestral gene: an unlikely scenario for the origins of translation that will not be dismissed.

BACKGROUND: Because amino acid activation is rate-limiting for uncatalyzed protein synthesis, it is a key puzzle in understanding the origin of the genetic code. Two unrelated classes (I and II) of contemporary aminoacyl-tRNA synthetases (aaRS) now translate the code. Observing that codons for the most highly conserved, Class I catalytic peptides, when read in the reverse direction, are very nearly anticodons for Class II defining catalytic peptides, Rodin and Ohno proposed that the two superfamilies descended from opposite strands of the same ancestral gene. This unusual hypothesis languished for a decade, perhaps because it appeared to be unfalsifiable. RESULTS: The proposed sense/antisense alignment makes important predictions. Fragments that align in antiparallel orientations, and contain the respective active sites, should catalyze the same two reactions catalyzed by contemporary synthetases. Recent experiments confirmed that prediction. Invariant cores from both classes, called Urzymes after Ur = primitive, authentic, plus enzyme and representing ~20% of the contemporary structures, can be expressed and exhibit high, proportionate rate accelerations for both amino-acid activation and tRNA acylation. A major fraction (60%) of the catalytic rate acceleration by contemporary synthetases resides in segments that align sense/antisense. Bioinformatic evidence for sense/antisense ancestry extends to codons specifying the invariant secondary and tertiary structures outside the active sites of the two synthetase classes. Peptides from a designed, 46-residue gene constrained by Rosetta to encode Class I and II ATP binding sites with fully complementary sequences both accelerate amino acid activation by ATP ~400 fold. CONCLUSIONS: Biochemical and bioinformatic results substantially enhance the posterior probability that ancestors of the two synthetase classes arose from opposite strands of the same ancestral gene. The remarkable acceleration by short peptides of the rate-limiting step in uncatalyzed protein synthesis, together with the synergy of synthetase Urzymes and their cognate tRNAs, introduce a new paradigm for the origin of protein catalysts, emphasize the potential relevance of an operational RNA code embedded in the tRNA acceptor stems, and challenge the RNA-World hypothesis.

Evaluation of anxiety, salivary cortisol and melatonin secretion following reflexology treatment: a pilot study in healthy individuals.

This pilot study sought to identify an appropriate methodology to investigate the impact of reflexology in healthcare settings. The study involved healthy volunteers to prevent unnecessary intervention to individuals who may already be experiencing health related trauma. Thirty participants underwent either reflexology or no treatment (control), in a cross-over experimental design. Self-reported anxiety (Spielberger STAI), cardiovascular parameters (BP and pulse rate) and salivary cortisol and melatonin concentrations were assessed before and after reflexology. Control data were obtained at the same time points in identical settings. Reflexology had a powerful anxiety-reduction effect ('state'; P<0.001) but no significant effect on underlying anxiety ('trait'). Cardiovascular parameters decreased (P<0.001). Baseline salivary cortisol and melatonin were not significantly correlated with STAI scores and did not change significantly following reflexology. Reflexology reduced 'state' anxiety and cardiovascular activity within healthy individuals, consistent with stress-reduction. Considering the connection between stress/anxiety and well being, the effects of reflexology may have beneficial outcomes for patients. These findings will be transferred to a study involving breast cancer patients where effects may be more pronounced particularly since cancer patients display disregulation of cortisol and melatonin secretion.

Plasma levels of genistein following a single dose of soy extract capsule in Indian women.

BACKGROUND & OBJECTIVE: Soy isoflavones are being used as therapy for menopausal syndrome in many countries. Marketed preparations show variability in bioavailability and there are variations in kinetics due to ethnicity and diet. Inspite of soy isoflavone being available in the Indian market there are no studies to show whether the preparation is likely to be effective in women. This study was carried out to determine circulating levels of genistein, a bioactive soy isoflavone, in Indian women after a single dose of soy extract. METHODS: Six healthy vegetarian women volunteers, between 36 and 62 yr and with a mean body mass index (BMI) 25.01+/-2.02 (kg/m2), were enrolled after an informed consent. Women with antibiotic or Soy food intake within 1 month of study were excluded. A single dose of standardized soy extract capsule containing 64.12 mg of total isoflavones (genistein content equivalent to 31.76 mg) was ingested under supervised fasting condition and multiple blood samples were collected at 0, 1, 2, 4, 6, 8 and 24 h. Genistein levels were measured by high performance liquid chromatography (HPLC) method with a detection level of 2.5 ng/100 microl of injection volume. The intra- and inter-assay coefficients of variation were < 5.32 per cent. RESULTS: Genistein was detected (10.3 to 16.2 ng/ml) in 3 volunteers in baseline samples. Within one hour genistein levels rose from 42 ng to 215 ng/ml with a maximum concentration of 117 to 380 ng/ml at 4 to 8 h. A secondary peak suggestive of enterohepatic circulation was seen between 4 and 6 h in 2 out of 6 volunteers. The mean Cmax was 315.5 +/- 57.1 ng/ml. All women had detectable levels from 25.2 to 109.3 ng/ml at 24 h. INTERPRETATION & CONCLUSION: Our study showed adequate circulating levels of genistein in Indian vegetarian women after a single dose of soy extract. Variability in plasma levels of the soy isoflavones may explain differences in responses to therapy.

The surgical management of patients who achieve a complete pathological response after primary chemotherapy for locally advanced breast cancer.

AIMS: Our aim was to investigate the role of minimal surgery in patients with locally advanced breast cancer (LABC) who achieve a complete pathological (pCR) response to primary chemotherapy (PC) and evaluate subsequent local recurrence (LRR), disease free survival (DFS) and overall survival (OS). METHODS: Between January 2000 and April 2005, 101 patients with operable LABC (T2, T3, N0 or N1, M0) who were not suitable for conservation surgery were treated with PC. Patients were treated with doxorubicin and cyclophosphamide for four cycles (100 patients) then four cycles with paclitaxel (91 patients). Post-PC surgery consisted of multiple core biopsies and axillary clearance for patients with a complete clinical and radiological response. If a pCR was confirmed no further breast surgery was performed. The remaining patients were treated with breast conserving surgery or mastectomy and axillary clearance as appropriate. Adjuvant radiotherapy was given to all patients. RESULTS: Breast conservation was possible in 60% of patients. Overall, 20 patients achieved a pCR of which 16 were confirmed on core biopsies alone. All patients were followed-up for a mean of 33.5 months (95% CI, 30.3-36.7). There were 10 local recurrences, four following mastectomy, four after wide excision and two after core biopsies. There was no difference in DFS (chi square=0.18; p=0.67) or OS (chi square=0.67; p=0.41) between patients achieving a pCR and the remainder. CONCLUSIONS: The local recurrence rate of these poor prognosis patients is similar to other reported series but higher than in our previously reported series of patients managed according to the same protocol. Our current management therefore now includes pre-treatment marking and subsequent surgical excision.

The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican.

BACKGROUND: Benign prostatic hyperplasia (BPH) is characterized by a proportional increase in the size of the stromal compartment of the gland, involving alterations to extracellular matrix (ECM) components. Some of these changes have been associated with the activity and expression of transforming growth factor beta1 (TGFbeta1). Versican (chondroitin sulphate proteoglycan-2) is overexpressed in BPH and prostate cancer and potentially contributes to disease pathology. A sub-group of the ADAMTS lineage of metalloproteases possess versican-degrading properties and are potential regulators of proteoglycan accumulation associated with BPH. These enzymes have one major inhibitor in the ECM, tissue inhibitor of metalloproteinases (TIMP)-3. METHODS: The effect of TGFbeta on mRNA expression in prostatic stromal cells was determined by real-time qRT-PCR using primers to ADAMTS-1, -4, -5, -9, -15, versican, and TIMP-3. MMP-inhibitory potential (TIMP activity) of conditioned medium was measured using a fluorometric peptide substrate. RESULTS: Prostatic stromal cell cultures consistently expressed ADAMTS-1, -4, -5, -9, -15 and TIMP-3, in contrast to PC3, DU145, and LNCaP cells which failed to express at least two ADAMTS transcripts. In stromal cells, TGFbeta1 decreased ADAMTS-1, -5, -9, and -15 transcripts and increased ADAMTS-4, versican, and TIMP-3. TGFbeta also increased TIMP activity in conditioned medium. CONCLUSIONS: The induction of versican expression by TGFbeta in BPH stromal cells is in agreement with histological studies. The negative effect of TGFbeta1 on ADAMTS-1, -5, -9, and -15 coupled with increases in their inhibitor, TIMP-3 may aid the accumulation of versican in the stromal compartment of the prostate in BPH and prostate cancer.

Assessment of efficacy, safety and tolerability of fixed dose combination of telmisartan 40mg and hydrochlorothiazide 12.5mg in adult Indian patients with mild to moderate hypertension.

The objective of the study was to assess the efficacy, safety and tolerability of a fixed dose combination of telmisartan 40 mg and hydrochlorothiazide 12.5 mg in adult Indian patients with mild to moderate hypertension. A prospective, multicentric, open-label, non-comparative, phase IV study was conducted. A total of 353 patients of either sex, between 18- 65 years of age with supine blood pressure (BP) levels of systolic BP (SBP) of 140-200 mmHg and diastolic BP (DBP) of 95-114 mmHg were included. After a placebo run-in period of 2 weeks, each patient received a fixed dose combination of telmisartan/hydrochlorothiazide (40mg/12.5mg) once daily, for 8 weeks. Supine BP was assessed at the end of every 2 weeks. Tolerability and safety were assessed by physical examination, laboratory parameters and evaluation of adverse events. A total of 339 patients completed the study with 14 drop-out cases because of loss to follow-up. There was a significant fall (p<0.05) in both the SBP and DBP starting from the second week as compared to the baseline. Mean SBP had a significant reduction of 23.55 mmHg (15.0%) and 27.79 mmHg (18%) at the end of 6th and 8th week respectively, compared to baseline values. Mean DBP had also had a significant reduction of 12.51 mmHg (12.6%) and 15.17 mmHg (15.3%) at the end of 6th and 8th week respectively, compared to baseline values. This combination was well tolerated with only 3.9% of the total cases reporting mild adverse events like fatigue, dizziness, nausea, diarrhoea etc. The laboratory values were within normal limits. Fixed dose combination of telmisartan/hydrochlorothiazide (40 mg/12.5 mg) once daily has a significant therapeutic effect and a good tolerability profile in adult Indian patients with mild to moderate hypertension.

Efficacy and safety of nateglinide in the treatment of type II diabetes mellitus.

Nateglinide a new short-acting D-phenylalanine derivative represents a new chemical class of drugs for treating type 2 diabetes that is pharmacologically and therapeutically distinct from currently existing agents. Studies in normal patients and those with type 2 diabetes have shown that nateglinide reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. Nateglinide binds to and inhibits the K+(ATP) channel of the beta-cell, causing membrane depolarisation, with a subsequent influx of extracellular calcium that results in insulin secretion. A total of 105 patients in 5 centres with type II diabetes mellitus were taken according to the inclusion criteria and given drug treatment and were evaluated on their improvement in fasting and postprandial plasma glucose and glycosylated haemoglobin values for efficacy, besides physician's assessment of the overall safety and efficacy. Nateglinide in a dose of 60 mg before three main meals was given and increased to a maximum of 120 mg thrice daily over the first 3-4 weeks. Nateglinide had to be taken 10 minutes before meals. Duration of treatment was 12 weeks. The patients showed decrease in fasting plasma glucose from 2nd week onwards and reduction in glycosylated haemoglobin by 6th week onwards. Postprandial glucose reduction was also significant at the end of 12th week. The frequency of adverse effects was low and no serious adverse effects were encountered.

Invasive lobular carcinoma of the male breast: do we need to think of Klinefelter's syndrome?

Cancer of the male breast is generally seen in men over 60 years of age and, as in women, the commonest histological type is invasive ductal carcinoma. Invasive lobular cancers are seen very rarely because of the absence of lobules in the male breast. Genetic abnormalities such as Klinefelter's syndrome can increase the risk of breast cancer, and it is thought that there has to be some cytoarchitectural abnormality for development of lobular cancers in men.

Cyclospora cayetanensis--an emerging coccidian parasite.

Over the last decade increasing number of enteritis cases have been attributed to infection with a new coccidian sp that was named Cyclospora cayetanensis in 1993. Diarrhoea caused by this agent is clinically indistinguishable from cryptosporidiasis, isosporiasis and microsporidiasis but cyclospora infection are often very prolonged (upto 15 weeks) and may cause severe weight loss. Diagnosis is important because unlike diarrhoea caused by cryptosporidium and microsporidium, treatment with co-trimoxazole is effective. We report here a case of cyclosporiasis, to increase awareness of possibility of cyclospora infection in patients with prolonged diarrhoea. It should be considered in assessment of patients with unexplained prolonged diarrhoeal illness.

Delayed intracranial haemorrhage in head injury.

To determine the incidence of delayed intracranial haemorrhage and the indication for repeat computed tomography (CT), a one and a half year retrospective study was made. A total of 289 patients had CT scan for head injury of which 78 (26.9%) had multiple scans. Out of these, 5 patients developed delayed haemorrhages (one extradural, one subdural, and three intracerebral haematoma). The incidence of delayed intracranial haemorrhage in our series is small when compared with others. The main predisposing factors are decompressive surgery, hyperventilation and cerebral dehydration therapy. It is important to know when to repeat the CT scan. A review of the literature regarding this aspect is presented and compared with our protocol. Intracranial pressure monitoring plays an increasingly important role in the management of head injury and should be used to decide the patient requiring repeat CT. Follow-up CT without other indication is not necessary.

Transforming growth factor beta activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Sp1 consensus site.

Transforming growth factor beta (TGF-beta) causes growth arrest in the G1 phase in many cell types. One probable pathway for this growth inhibition is through the TGF-beta-mediated up-regulation of the cyclin-dependent kinase (CDK) inhibitor p15INK4B, which specifically inhibits the enzymatic activities of CDK4 and CDK6. An active cyclin D-CDK4/6 complex is required for pRb phosphorylation to allow the cell cycle to progress from G1 to S phase. To study the molecular mechanism of the p15INK4B induction by TGF-beta, we isolated a 780-base pair promoter sequence of the human p15 gene and inserted this fragment upstream of a luciferase reporter gene. When this construct was transiently transfected into HaCaT cells, luciferase activity was induced more than 10-fold upon TGF-beta treatment, indicating that the induction of p15INK4B expression by TGF-beta is partly exerted at the transcription level. Promoter deletion analysis revealed that the sequence from -110 to -40 relative to the transcription start site is capable of conferring the 10-fold induction by TGF-beta. Within this region there are three Sp1 consensus sites. Mutation of one of these sites, GGGGCGGAG, substantially reduced both the induction by TGF-beta and the basal promoter activity, whereas mutations in the other two Sp1 sites and the spacer sequences had little effect. In addition, gel mobility shift assay indicates that the transcription factors Sp1 and Sp3 bind to this Sp1 site. Taken together, these data suggest that a specific Sp1 consensus site is involved in the mediation of TGF-beta induction as well as the basal promoter activity of the p15 gene and that Sp1 and Sp3 transcription factors might be involved in this regulation.

Multi-drug resistance in salmonellae isolated from enteric fever cases at Porur--a semi urban area near Madras City.

A total of 249 isolations of Salmonella were made during 1991, of which 67.46 per cent were resistant to chloramphenicol. Resistance to ampicillin, co-trimoxazole and amoxycillin was higher (82.91, 77.69, 81.42 per cent respectively). Salmonella typhi was predominant agent forming 94.78 per cent and Salmonella paratyphi A caused the remaining infections. 44.98 per cent of the isolations were in children. This outbreak has been discussed in the light of other reports from India.

[Discrimination of geographic strains of periodic Brugia malayi by the cuticular ornamentation of the male]. / Discrimination de souches géographiques de Brugia malayi périodique par l'ornementation cuticulaire des males.

A comparative study of five periodic human strains of Brugia malayi, originating from India, China, Korea, Malaysia and Indonesia, is given. This morphological analysis is based on males; the "standard" characters (oesophagus, papillae, spicules...) appear identical. On the contrary, the cuticular ornamentation of the posterior region--which is composed of the area rugosa and of a system of bosses and constitutes a secondary non-skid copulatory apparatus--differs following the geographical origin of the strain. A key is given, based on this character. 1(2) At 800-1,200 micron from the tip of tail, numerous cuticular bosses present on the right side of the body (fig. 2 and 8 B). 2(1) At 800-1,200 micron from the tip of tail, cuticular bosses absent or scarce on the right side of the body (fig. 8 D). 3(4) At 1,800-1,200 micron from the tip of tail (fig. 4), scarce and slightly projecting cuticular bosses on the dorsal side of the body contrasting with well projecting lateral cuticular bosses (fig. 9 E and F). Anterior extremity of the area rugosa made by a few stripes of tiny bosses linked transversally (fig. 9 A). 4(3) At 1,800-2,200 micron, numerous cuticular bosses on the dorsal side of the body (figs. 5, 6 and 7). Anterior extremity of the area rugosa made by the stripes of longitudinal rods (fig. 9C). 5(6) Oblong transversally stretched cuticular bosses on the dorsal and left sides of the body, anteriorly to the area rugosa (fig. 5); big oblong bosses on the left side (fig. 9 B). Transversal wrinkles and stripes of rods absent on the dorsal side of the body. 6(5) Round cuticular bosses on the dorsal and left sides of the body anteriorly to the area rugosa (figs. 6 and 7): no big oblong bosses on the left side. Transversal wrinkles or stripes of rods present on the dorsal side of the body (fig. 9 D). Nomenclaturally, such differences could be used in defining different taxa, but it could be useful to perform "blind determination" (material without labelling), to study conveniently the morphology of microfilariae (often an excellent indication for speciation in that group of Nematodes) and, evenly, to proceed to parallel studies on isoenzymes. However, whatever could be the taxonomical conclusion, the differences observed in Brugia malayi originating from different regions appear to the sufficient to consider the existence of four distinct diseases.