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Pre-Implantation Genetic Diagnosis: An innovative technique with exciting potential

Mr. Paul Serhal. MRCOG
Medical Director
Hon. Consultant/Senior Lecturer 

PGD is a very early method of prenatal diagnosis for those couples who are at risk of transmitting an inherited disease to their children. For such couples to produce a healthy family, the main option open to them is for the woman to become pregnant and undergo prenatal diagnostic test, such as amniocentesis or chorionic villus sampling (CVS) at between 12-16 weeks of her pregnancy.

If the foetus is found to be affected, the couple have to decide if they wish to continue with the pregnancy. Using PGD we perform the diagnostic test before implantation, thus avoiding the need for recurrent termination of pregnancies.

For PGD the couple undergo routine IVF procedures and when the embryos are between 6-10 cells (3 days after the egg collection) 1-2 cells can be removed (embryo biopsy) and used for the diagnosis. Unaffected embryos can be transferred back to the woman so that pregnancy is started knowing that the foetus will be unaffected with the familial disease.

The Human genetics and Embryology Group at UCL, under the direction of Mr. Paul Serhal, has been performing the diagnosis of sex for patients carrying X-linked disease (which will only affect male children) since 1991 and in 1195 were the first group to perform PGD for patients carrying chromosome abnormalities.

UCL Centre for PGD will undertake PGD for embryo sexing to avoid X-linked disease (such as Duchenne muscular dystrophy and haemophilia), for the detection of chromosome abnormalities (such as translocations and gonadal mosaicism) and the diagnosis of severe single gene defects (such as cystic fibrosis, b-thalassaemia and sickle cell anaemia).


The UCL group is one of the leaders in this field, analysing chromosomes using a procedure called fluorescent in-situ hybridisation (FISH).


Analysis of Oocytes

The work on oocyte chromosomes shows that abnormalities originating from oocytes account for a large proportion of spontaneous miscarriages. It is already known that the chance of producing a chromosomally abnormal foetus increases with age, an effect called 'age-related aneuploidy'. Therefore, women over 35 years of age are offered a prenatal diagnostic test to ensure their pregnancy is chromosomally normal.


Analysis of Sperm

Examining chromosomes from sperm samples is problematic as the chromosomes are tightly packed within the sperm head. Using the FISH technique, the sperm nuclei have first to be de-condensed so that the probes can gain access to the chromosomes.

Analysis of Embryos

The examination of the chromosomes of human embryos is a major interest of the Human genetics and Embryology Group and a research team is currently involved in the investigation of early human development through such examinations. The results emerging from this work may also have important consequences for IVF and PGD.

The embryos being analysed come from several groups of patients: those with repeated IVF failure, repeated miscarriage, those showing abnormal oocyte or embryo development and patients undergoing PGD.

Brussels, the capital of the European Union, has hosted the 2nd EBCC organised by EORTC, EUSOMA and Europa Donna. There were approximately 500 presentations¹ that addressed, in addition to the recent advances in the field of breast cancer, other issues relating to the implementation and dissemination of such advances.  

Several presentations focused on breast cancer screening for women aged 40-49 years. Evans et al presented a meta-analysis of all randomised trials of screening mammography in women aged 40-49 years at randomisation. The meta-analysis revealed a significant reduction in mortality (RR=0.84, 95% CI=0.72-0.98). The reduction in mortality increased to 23% when the weaker Canadian trial was excluded. One poster described the preliminary results of participation, referral and detection rates in women aged 70-75 years (biennial mammography) invited for screening by the Dutch breast cancer screening programme. The authors observed that the referral rate (18 per 1000 screened women), detection rate (11.1 per 1000) and PPV of the screen-test (69%) were favourable in women aged 70-75 years compared with women aged 60-69 years. Fracheboud et al from the Dutch breast screening programme examined the occurrence and stage distribution of interval cancers in women who were initially screened during 1990-1994. The authors identified 2103 interval cancers with a detection rate of 0.96 interval cancer per 1000 women - years of follow up. The interval cancers had a more favourable tumour size distribution. Interval cancer accounted for 26% of the underlying incidence in the first year after initial screening and for 48% in the second year suggesting that screen detection of breast cancer can be improved further in subsequent screens. The need for quality assurance in breast cancer screening programmes was emphasised by several speakers. In fact, the 3rd edition of the European Guidelines for Quality Assurance in Breast Cancer Screening clearly states that data collection and audit of surgical treatment is mandatory. Ponti et al examined the feasibility of monitoring the management of screen-detected breast lesions in 953 patients operated on during 1997-1998 in 11 European centres. The authors found the QT 2.3 Audit System more complete and provided a friendly data analysis environment compared with the BASO 2.0 Breast Unit Database. The latter was found to be more useful for producing clinical reports. Dr Distante and colleagues from Italy reported a good compliance rate with quality assurance indicators using the QT 2.3 Audit System within the Italian Breast Cancer Screening Network.  

Two further posters from the Dutch screening programme reported a significant benefit associated with adding craniocaudal views to conventional one-view screening mammography. Two-view mammography seems to increase the test specificity, however its effect on sensitivity remains controversial.  

Kolasinska et al reported that scintimammography with Tc-99m (SMM) was accurate and cost-effective in detecting recurrent breast cancer. In a series of 38 patients with recurrent disease, the authors observed a sensitivity of 79%, a specificity of 83%, a PPV of 83% and a NPV of 79% compared with 29%, 75%, 55% and 50% respectively for conventional mammography. Piccolo et al reported an overall accuracy of 91% for SMM in the diagnosis of malignancy in patients presenting with mammographic microcalcifications not associated with a mass lesion (n=121). The same institution reported their experience with SMM in more than 4000 women and found that the technique was safe, cost-effective, well-tolerated and accurate. It was particularly useful in cases where the mammographic pattern was indeterminate. The use of SMM as a complementary modality to conventional breast imaging is likely to increase in the near future.

In a series of 82 patients presenting with a bloody nipple discharge, Yoshimoto et al found MR mammography 4.5 times more accurate than standard mammography in detecting breast cancer not associated with microcalcification (MCC). However, the accuracy was similar when MCC was present.

Dr Hieken and colleagues from Chicago reported their experience using a hand-held 7.5 Mhz linear array ultrasound (US) transducer in 1000 women attending the breast clinic. The authors found this nodality a useful adjunct to clinical and mammographic examination. US features suggestive of malignancy included an AP to lateral dimension ratio of 1, heterogenous hypoechoity (71% malignant), irregular posterior shadowing (63% malignant), and fuzzy/jagged margins (49% malignant).

Auerbach et al presented interesting data on the role of p43-positive lymphocytes in the peripheral blood as a marker of early breast cancer (n=96). Using a cut-off level of 2%, the authors observed a sensitivity of 89.7% and a specificity of 89.1% for the detection of early breast cancer. Such a marker may prove useful in women with indeterminate mammographic findings.  

Bijker et al discussed the risk factors for recurrence and metastasis after breast conserving surgery (BCS) for DCIS in the EORTC trial 10853 (n=863). After a median follow up of 5.4 years and central pathological review, the authors observed that age younger than 40 years (HR=2.14, P=0.02), symptomatic presentation (HR=1.80, P=0.008), positive margins (HR=2.07, P=0.0008), solid and cribriform growth pattern (HR=2.68, P=0.012) and omission of adjuvant radiotherapy (HR=1.74, P=0.009) were significantly associated with increased local recurrence rate. Furthermore, patients with poorly differentiated DCIS had a significantly higher incidence of distant metastasis after invasive recurrence (HR=6.57, P=0.01). Cutuli and colleagues reported similar results in 716 women with pure DCIS treated in 7 French Cancer Centres. The authors found that young age (<40 years) and involved margins were significant predictors of local recurrence and that 20.6% of patients with invasive recurrence developed distant metastasis.

Professor R. Holland from the Netherlands addressed the issue of surgical margins assessment in a key lecture. Professor Holland’s recommendations included correct orientation of the resection specimen by the surgeon, inking of the entire specimen surface by the pathologist, X-ray of the intact specimen and then subsequent X-ray of the specimen after sectioning it at 5 mm intervals.  

The sentinel node biopsy (SNB) in patients with early breast cancer was addressed by several speakers. Beets and colleagues from the Netherlands reported the results of a multicentre validation study involving 7 hospitals in the province of Limburg (1996-1999). The authors observed significant differences among the various centres with success rates varying from 69% to 100%. The authors concluded that the minimal number of cases required in order to achieve a sensitivity that exceeds 90% was 50 cases and emphasised the need for close co-operation and feedback between the various disciplines involved in the procedure. Dr Bourez described the design of the EORTC-AMAROS trial. This is a phase III randomised multicentre study - comparing a complete axillary lymph node dissection against axillary radiotherapy (RT) in patients with a positive SNB. Participating centres are required to perform 30 SNB procedures with comparative axillary node dissection with a minimum of 27 patients with accurate SNB idenification and no more than 1 false negative result is allowed. Subsequently the centre is site-visited and all cases are reviewed. The learning curve can be extended by steps of 10 patients until the last 30 patients fulfil the criteria. Centres willing to participate in the study can contact Dr R. Bourez in the Netherland Cancer Institute in Amsterdam. In a prospective study of 280 patients undergoing the SNB, Dr van de Ent and collegaues performed internal mammary node (IMN) dissection in 48 patients and detected IMN metastasis in 25% (12/48) of cases. Three of these patients (6%) had a negative axilla. Since adjuvant chemotherapy is increasingly given to women with negative axillary nodes, dissection of the IMN in this study altered adjuvant treatment only in 1 patient with a T1 tumour (approximately 1%), therefore casting some doubt over the value of this procedure which has additional morbidity (namely pneumothorax), cost and scar. However, further studies are required to assess this technique. In a different presentation,the same authors reported that previous excisional biopsy did not reduce the accuracy of the SNB identified by the blue dye and radioactive tracer techniques (n=88, sensitivity=100%, identification rate=99%). Dr Ahlgren and colleagues reported their results in 416 patients undergoing 5 axillary node sampling. The authors observed a sensitivity of 97.3% and a NPV of 98.5% and suggested that this technique could provide an alternative to axillary node clearance and SNB.  

Dr Horiot presented the results of the EORTC “boost versus no boost” trial which involved 5569 patients. After complete excision of the primary tumour (n=5318) the authors observed a significantly lower local recurrence in the group receiving a boost dose of 16Gy after BCS (6.8% versus 4.3%, P<0.0001). This finding may change the current practice in many centres around the world. Professor R. Blamey presented an update of the BASO II trial. At a median follow up of 2.1 years, the authors observed that adjuvant radiotherapy did not significantly decrease the incidence of local recurrence after adequate local excision of T1 tumours of grade I or special histological type. The annual local recurrence so far is 0.8% for the no-RT group and 0.6% for the RT group. However, in view of the limited follow up duration, great caution should be exercised when interpreting such premature data.  

Dr van der Hage from the Netherlands presented the results of EORTC trial 10854 regarding the role of perioperative chemotherapy in early breast cancer after 9 years of follow up. The authors found that one short intensive course of FAC significantly reduced the incidence of locoregional recurrence (HR=0.67, P=0.001) and improved DFS (HR=0.88, P=0.03) but not overall survival in both node-negative and node-positive patients.

In a special symposium dedicated to adjuvant systemic therapy, Mouridsen presented an overview of anthracyclines. The meta-analysis showed that anthracycline-containing regimes were associated with a modest but significant benefit over CMF schedules. Epirubicin was superior to doxorubicin in terms of toxicity and efficacy. The results of ongoing trials examining the role of epirubicin containing regimes in elderly patients are currently awaited with interest. Professor Hortobagyi from the MD Anderson Cancer Centre addressed the potential role of taxanes in the adjuvant therapy setting. The CALGB9344 trial reported a 22% reduction in the odds of recurrence and 26% reduction in mortality at 30 months in patients treated with 4 courses of doxurubicin and cyclophosphamide (AC) followed by 4 courses of paclitaxel compared with 4 cycles of (AC) only. The results of the NSABP B-27 trial comparing 4 courses of AC followed by 4 courses of docetaxel to AC only are currently awaited with interest. The results of the EORTC trial 10902 assessing the benefits of preoperative chemotherapy in 698 women with early breast cancer. Dr van der Hage reported that after a median follow up of 4.5 years preoperative chemotherapy (4 cycles of FEC) significantly increased the rate of BCS but had no impact on DFS or OS compared with post-operative chemothearpy (4 cycles of FEC). These results are consistent with previously published reports.  

On the hormonal therapy front, Professor Jonat presented an update of the ZEBRA trial comparing Zoladex (3.6 mg for 2 years) versus CMF (6 cycles) as adjuvant therapy in pre / perimenopausal women (<50 years) with node-positive breast cancer.

In ER-positive patients (73%), Zoladex was equivalent to CMF in terms of DFS and OS. However, Zoladex was superior to CMF in toxicity and tolerability. Although menopausal symptoms were more frequent in the Zoladex group, such symptoms were more likely to resolve after cessation of therapy. These early efficacy results are encouraging and suggest that Zoladex alone offers a safe and well tolerated alternative to chemotherapy in such patients.  

On behalf of the International Breast Cancer Group, Dr Mouridsen presented the preliminary results of a phase III randomised controlled trial comparing letrozole (2.5mg o.d.) with tamoxifen 20mgs o.d.) in 907 post-menopausal women (65% were ER and / or PR positive) with locally advanced or metastatic breast cancer. The authors observed that letrozole significantly prolonged the median TTP (41 weeks versus 26 weeks, P=0.0001). Robertson et al reported similar results when comparing anastrazole with tamoxifen (median TTP=34 and 28 weeks respectively). Such results suggest that third generation aromatase inhibitors are likely to replace tamoxifen as a first-line therapy in post-menopausal women with ER and / or PR positive locally advanced or metastatic breast cancer. It remains to be seen whether letrazole (median TTP=41 weeks) is superior to anastrazole (median TTP=34 weeks) in this setting. In fact this question is currently the subject of an ongoing trial. Professor Dowsett from the Royal Marsden Hospital (UK) reported that letrazole achieved a more complete inhibition of whole body aromatisation than anastrazole in a double-blind randomised cross-over study involving 12 postmenopausal women. The residual aromatase activity was 3 times higher with anastrazole.  

The results of the two pivotal trials examining the role of Herceptin in the treatment of metastatic breast cancer overexpressing Her-2 were presented during a satellite symposium sponsored by Roche. However, new data on the pharmacokinetics of the drug was presented by Dr Lieyland-Jones from Canada. The authors examined the pharmacokinetics and safety of 3 weekly Herceptin. The early data showed that such a regimen compared favourably with those of weekly Herceptin. This finding may have significant implications regarding future trial designs. If 3 weekly Herceptin proves to be equally effective to weekly Herceptin, then patient’s quality of life can improve further. Several studies examined the role of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in detemining Her-2 status in breast tumours. Dr Mass from Genentech presented the concordance rates between FISH and clinical trail assay (CTA) in 623 samples randomly selected from the two pivotal Herceptin trials. FISH positivity was observed in 4.2 % , 6.7%, 23.9% and 89.3% of CTA 0, 1+, 2+ and 3+ respectively. Conflicting results regarding the best antibody to use in determining the IHC status of Her-2 were presented by Falo et al and Bartlett et al respectively. The former found the monoclonal antibody CB11 more reliable than the Dako polyclonal antibody compared against FISH, whereas Bartlett et al reported a higher accuracy for the polyclonal antibody (87.4%) compared with CB11 monoclonal antibody (83.8%). In view of such conflicting results and the significant inter-observer variation, perhaps FISH testing should be performed as the gold standard. Such a move will require rapid development of local expertise in breast cancer centres.  

In a special session dedicated to lymphedema, Dr Brorson from Sweden presented the results of liposuction in 64 women with lymphedema of the arm after previous breast cancer treatment. All patients used compression garments post-operatively. At 6 years of follow up the treated arm was smaller than the contralateral arm (relative volume = 95%). Liposuction seems to be a promising modality in those women with fat hypertrophy secondary to impaired lymph flow.  

Regarding the role of prognostic parameters Dr Masuda from Japan reported that CEA-specific RT-PCR analysis of histologically negative axillary modes was an independent and significant predictor of both DFS and OS (HR=3.99 and 4.29 respectively) in a series of 129 women with node-negative breast cancer. Dr Hansen (Denmark) and Dr Kato (Japan) reported that angiogenesis was an independent prognostic presdictor of clinical outcome in patients with breast cancer. Dr Hammer (Austria) and Dr Kroman (Denmark) reported that medial tumour location was a significan predictor of worsened clinical outcome. Such patients should be perhaps considered for adjuvant systemic therapy and / or RT to the IMNs especially if the axillary nodes are negative. The EORTC trial 22922/10925 is likely to clarify this issue in the future.

The identification of predictors of response to systemic therapy was the focus of several abstracts. Bojar and colleagues (Germany) demonstrated the feasibility of using jet-needle biopsies for large scale gene expression profiling (array hybridization) in order to monitor early response to pre-operative chemotherapy. Topoisomerase II alpha was found to be a significant predictor of response to anthracycline-based chemotherapy in 481 women with early breast cancer (Dileo et al). In the advanced setting, Foekens and colleagues showed that elevated levels of VEGF in the tumour were a poor predictor of response to tamoxifen or chemotherapy.  

Finally, Sir Richard Peto from Oxford presented the updated results of EBCTCG worldwide overview (2000). The overview confirmed the previously established evdience regarding the benefits of adjuvant hormonal therapy and chemotherapy. However these benefits seem to increase with longer follow up (>10 years). It was intriguing to observe that adjuvant RT which decreased locoregional recurrence in the first 4 years after surgical treatment by two thirds seemed to significantly reduce mortality by one sixth in the subsequent 10 years (years 5 to 14). However the non-breast cancer-related mortality increased by one third after 15 years of follow up in patients who had received adjuvant RT.

The 3rd EBCC is due to be held in Barcelona (19-23 March 2002).

Dr Asma B OMER BSc, SRD, MSc, PhD
Consultant in Human Nutrition & Diet Therapy
Harley Street, London.
United Kingdom

THE SCENARIO
The last few decades have witnessed ongoing technological advancements, which have
enhanced our daily life in a number of ways. Similarly, the science of nutrition has
developed with a competitive speed. However the number of those who have become
overweight and becoming obese is increasing year by year. Despite the vast number of
books written on diet, slimming and weight loss strategies, obesity and overweight
related ailments have yet to take a reversed mode. Food is abundant in limitless
quantities and varieties and similarly information on healthy eating, but people are not
getting any healthier, though living longer. The question needs to be addressed here is
why?.

THE SCOPE OF THE PROBLEM
In spite of the general understanding of the ‘healthy eating message’ of eating ‘less-fat
and more fibre’, which we all subscribe to, the latest statistics from the UK Department
of Health, showed that 20% of women and 17% of men in the UK are clinically obese
(BMI ³30). Furthermore 40% of men and 33% of women are currently overweight (BMI
25 to <30). This is a large number of the UK population with over 50% of women and
60% of men are either obese or overweight. Undoubtedly weight increase is now
reaching an epidemic level in Britain and reportedly so in the USA.
This trend has been greatly influenced by the modern age, which is characterized by
automation and information technology. The machine, which has become an essential
part of our everyday life during the past few decades (e.g. the car, lift, escalator, washing
machine, dishwasher, computers, etc.), has taken over the role of habitual physical
activities. Such technological advancements have on one hand enhanced our life and
increased the average life expectancy but on the other hand increased health-related risks.
Our sedentary lifestyle has contributed to a predictable level of physical inactivity with
resultant positive energy balance and weight gain as well as difficulty in losing excess
weight.
When taking into account the health-related risks of clinical obesity (BMI ³30), including
cardiovascular diseases, type II diabetes, arthritis, and some forms of cancer, strategies
other than those called for during the last 3 decades are urgently needed. A multi-faceted
approach, that looks at the individual as a whole, including his/her lifestyle factors rather
than just focusing on one single dietary factor should be adopted in order to achieve a
long lasting outcome.
In my view there are two operating factors; the first is lack of physical activities and the
second is an increase in the average consumption of food. The change in the home
environment is associated with more time for passive entertainment (e.g. watching TV,
using a computer, surfing the internet) and less time for outdoor activities (such as
walking, swimming, running, etc). Cooking and food preparation are no longer a priority
to most families. Instead, ready-prepared meals, fast foods and tempting restaurants
meals (all widely available at affordable prices) have replaced traditional family meals.
In addition, attractively packaged and well-presented foods are displayed in high-street
supermarkets and health food shops all year around. This abundance of food is combined
with regular promotional offers and strong advertising through all types of media.
Hence, encouraging people to consume more than they need, mostly through passive
eating such as snacking and picking.
It seems that we manage to add years to life but not life to years. One would, therefore,
wonder whether counting calories and grams of fat, and focusing merely on sliming
rather than healthy eating is the answer. Or, are there any underlying factors contributing
to what statistics is indicating? There appears to be too many hypotheses and not definite
answers, and people at all levels seem to be more confused than ever about what to eat
and what to avoid.

THE DIETING SAGA
Most dieting book emphasis reducing calorie intake, mostly via calorie counting, and do
not encourage exercise as a mean of increasing calorie deficit and hence achieving a
steady weight loss. The success of these diets is often judged by how much weight is lost
and how quickly rather than how safe and how long the weight loss can be maintained.
The truth is that there is no magical treatment or a quick fix formula. The notion of
dieting itself implies restriction and to some extent deviation from what is considered to
be normal and healthy. It leads to confusion as to what is a healthy diet since most
people think of a slimming diet as a healthy diet.
It is now well recognized that the increase obesity and overweight, together with their
health-related risks, cannot be solved solely by dieting. Although it is a customary that
every New Year comes with new ventures in dieting methods, the proportion of those
who are getting fatter and heavier is more than doubled since the eighties. It is
astonishing that we still market, sell, and buy dieting books in ever increasing numbers,
as a number of clever personnel (including highly qualified professionals), agents and
companies continue to maximize their profits at the expense of the consumer quest for
that miracle formula which will see the shrinking of their adipose tissues and bulk up
their lean tissue mass.
Important components of energy balance such as energy expenditure, represented by
physical activities, is scarcely addressed in these dieting books. In my view, and based
on my experience in this field, both sides of the equation (i.e. energy intake, represented
by food and drink and energy expenditure in the form of habitual physical activities and
physical exercise) need to be taken seriously and with equal importance. What is also
important for the success of any weight management program is a gradual and continual
incorporation of corrective measures, being changes in eating habits or habitual physical
activities, into the individual’s lifestyle.
It appears that the only true beneficiary from dieting regimens are the authors of
thousands of dieting books, currently circulating in an ever booming market, plus those
who market these books and sell them. However, those who follow these dietary
regimens usually experience a short-lived benefit, confined to the designated period for a
particular dietary regimen, and temporary short falls on their weighing scales.
WHAT IS WRONG WITH CALORIE COUNTING?
One of the major drawbacks of calorie counting, often promoted in dieting, is that it
distracts attention from other essential nutrients and consequently renders them
unimportant. It should be born in mind that the body needs about six essential nutrients.
These are fat, protein, carbohydrate, vitamins, minerals and water, each with a specific
function and designated role. What is also important is the synergy between various
nutrients (e.g. between vitamins and/or minerals). Therefore, when assessing the
healthiness of any diet, it might be worthwhile to ask questions such as:
Does it add value to health?
Is it nourishing, balanced and varied?
Is it adequate to the individual needs?
Is it free of additives, flavouring and colouring?
Does it contain any artificial sweeteners, preservatives etc?
Does it contain a GM product and/or high levels of pesticides?
How much trans and /or hydrogenated fat it contains per portion?
Is it for suitable that individual need?
The above questions may be of some relevance to health and well-being of almost all
individuals, regardless of age or health status, and maybe more meaningful than just
concentrating on how much calories and grams of fats the food contains.
If we were to follow the same format described in dieting books, which has persisted over
the years, we should then be asking how many milligrams of Calcium or Vitamin E a
product does contain.
In addition, calorie counting tends to shift the balance towards quantity rather than
quality or type even though the later are of equal or more significance when it comes to
fat related illnesses. It encourages certain sectors of the community, usually women and
teenage girls, to base their food choices solely on the fat and calorie content cited on the
food label without paying enough attention to the rest of the nutrition information or list
of ingredients as a whole.
Furthermore, counting calories per say may lead to unintentional nutritional imbalances,
which could manifest themselves as sub-clinical nutritional deficiencies. For example, an
average daily requirement for energy of 1500 kcal can easily be met by consuming a bar
of chocolate, a packet of crisps, a big Mac, a can of fizzy drink and an ice cream. Such a
way of eating may well satisfy the projected calorie demand, but it may fall short of
meeting the needs for all the essential nutrients. Overall it would not take into account
important dietary factors such as meal patterns, nutritional adequacy or particular
individual's needs. A point to remember is that children have different nutritional needs
to adults. Thus, applying the general healthy eating guidelines set for adults to children
can be detrimental to their health. In short, the fat and calorie saga not only has taken the
joy out of food, but also created an obsession with dieting, which is hard to overcome.
The law of thermodynamics still stands: 'energy can neither be created nor destroyed'.
However, the fact that excess food energy is stored as fat regardless of the source is
generally over-looked.

THE WAY FORWARD
My belief is that in order to counteract such forces imposed upon us by the modern age,
our attitudes towards foods, nutrition and health need to change accordingly. We need to
think in terms of energy density as well as moderating the quantities of the food we
consume, and be selective when it comes to quality. Our diet needs to be practically
varied, balanced and adequate to the individual, taking into accounts individual's lifestyle
factors and thinking in terms of health and weight management rather than slimming and
weight loss.
The question is how we (as scientists, health care professionals, fitness experts, policy
makers etc.) convince the public at large (obese, overweight or otherwise) that the above
message is simple, effective, attainable, less frustrating and long lasting. In another
word, how can we win back the dieting battle?
We can continue to debate this issue for decades to come, but this will not solve the
problem of horizontal growth and the gradual increase in the waistline, without taking a
realistic and wholesome approach that reverts from dieting. What is needed is an
initiative based on sound science and common sense; i.e. a weight loss strategy or
strategies that take into account all factors, governing and surrounding the individual's
lifestyle. So far, most of the well-publicized weight loss strategies and dieting books
emphasize only dieting with little or no consideration to sustainable physical exercise,
which impact weight loss, weight maintenance and the prevention of weight gain.
It may be the time for the public at large to realize that controlling food intakes,
separating protein from carbohydrate or creating new modes of eating (a high protein
diet, green and red days etc) that are not conducive to most people's daily routine, have
all failed in achieving a sustained weight loss. My experience showed that a collective
approach, which incorporates physical exercise and tackling issues such as inactivity,
along with a healthy eating approach that emphasizes 'balance, moderation and variety'
has proved to be not only effective, but also educational with long lasting health benefits
at all stages of weight management.
Finally, the answer may lie in what people do not do rather than what they eat!

COULD CORONARY ARTERY BYPASS GRAFT SURGERY FOR MULTI-VESSELS DISEASE BE PERFORMED WITHOUT THE HEART/LUNG MACHINE?*

M AMRANI
Senior Lecturer/Consultant Cardiac Surgeon
Royal Brompton & Harefield NHS Trust
Harefield Hospital
Harefield, Middlesex UB9 6JH

The conventional approach to coronary artery bypass graft surgery has been the use of the heart/lung machine. This has been associated with cardiac arrest in order to have still surgical feel. Both the heart/lung machine and controlled cardiac arrest have significant side effects which could be detrimental in some patients. Over the last years there has been a move to minimally invasive surgery which consists, in those category of patients, of avoiding the heart/lung machine and therefore its side effects.

Performing coronary artery bypass graft surgery from multi-vessels disease without the heart/lung machine presents two major challenges. Whilst the heart is beating there is a need to stabilise the portion of the cardiac muscle where the target vessel is located. The second challenge is the approach and access to the vessels located at the back of the heart, namely the circumflex artery and the right coronary artery. In order to reach them the heart needs to be lifted upwards, which produced a great deal of kinking and torsion of the great vessels. This in turn generates profound haemodynamic alteration. Using the new generation of stabiliser, as well as adding a few personal modifications, we have managed to operate on over 100 patients who presented with significant three vessels coronary artery disease. It was a complete shift from the conventional approach using cardiopulmonary bypass towards off-pump beating heart surgery. Although only a controlled study comparing conventional to the new technique would allow us to establish the real benefit, the results obtained in this series of patients operated on with the new technique compares very favourably in terms of outcome. We believe that this technique could be beneficial in difficult patients, namely elderly patients, patients with borderline renal failure and respiratory insufficiency.

* Summary of a Lecture given by Mr Amarani at the seminar" Internet and medicine 2000" organised by Doctorinternet in London on the 27th January 2000

By:Nabil Jarad PhD, MRCP, Consultant Respiratory Physician.

Up till now anti asthma medications are classified as either relievers an example of which are salbutamol Inhaler (Ventolin) or aminphylline tablets or as preventers such as inhaled steroids (Becotide, Pulmicorte).
Little has changed in asthma management during the last twenty years. More recently a new class of medications has been introduced. They have the advantage of being both relievers and preventer. To date three drugs are licensed:
montileukast (singulair),
Zafirleukast (Accolate) and
Pranleukast.

These medications act by blocking the action of substances called
leukotrines, and therefore called leukotrine antagonist.
Leukotrine are powerful airway muscle constrictors and has a strong
inflammatory action. By blocking their action, both a bronchodilator effect and an anti-inflammatory effect are achieved.

Singulaire can be taken as once daily and Accolate twice daily. They have shown to be very effective in:

• controlling asthma symptoms,
• reducing the requirement of inhalers,
• reducing night cough, wheeze and awakening,
• reducing morning chest tightness.
  

In young asthmatics these medications are particularly effective against exercise- induced asthma. They are particularly effective in a rare condition called aspirin sensitive asthma.
It is not clear yet whether this class of drugs is useful in severe asthma when the asthma is steroids-dependent. In this situation they should not be used instead of inhalers or steroid tablets without doctors advise.
Also it is not clear whether these medications are effective in
smoking-related lung disease such as bronchitis and emphysema.
The side effects are minimal. Nausea and headaches are the commonest side effects, but they are only seen in about 3% of cases.

All leukotrine antagonist are taken orally. Their drawback is that they are still expensive. The daily cost is almost five times as inhaled steroids.

By: Brian Glenville, MS FRCS Consultant cardiothoracic surgeon
St Mary`s NHS Trust, London

Taken and amended by the Author from the British Medical Journal BMJ. Exclusively to Doctorinternet

Coronary artery bypass grafts, have come a long way since the mid-1960s. Nevertheless, it remains a major operation with significant complications, and surgeons have sought new ways of reducing the insult to the patient. A variety of minimally invasive techniques offer some promise.
The cardiopulmonary bypass circuit has improved, but important pathophysiological consequences still remain for the patient. A 50 year old man has a 0.7% chance of suffering a stroke on cardiopulmonary bypass, and the risk rises to 8% in an 80 year old.1 As the average age of patients undergoing coronary artery bypass grafts continues to rise, this is important.

Apart from stroke, other more subtle changes, including memory loss and mild personality change, are also common. Among patients with renal impairment before surgery, the insult of cardiopulmonary bypass will push around 16% into acute renal failure.2 Haematological dysfunction, immunological suppression, and pulmonary disease are just some of the other undesired occasional consequences of cardiopulmonary bypass.
Two main "competitive" procedures have emerged from surgery on single vessel disease not amenable to angioplasty: minimally invasive direct coronary artery bypass (MIDCAB) and port access coronary artery bypass (PORTCAB). In both types the left anterior descending artery is approached by making a small lateral thoracotomy between the ribs, which provides surprisingly good visualisation. In port access coronary artery bypass the patient is then placed on cardiopulmonary bypass, typically via the groin vessels, and the anastomosis can be performed on a still quiet heart. In minimally invasive direct coronary artery bypass no cardiopulmonary bypass is used at all, and the surgeon performs the anastomosis on a beating heart using a platform or stabiliser. Stabilisers may be paired suction arms or gripping metal "skis" that sit astride the artery and make that part of the heart relatively immobile.

Single vessel disease represents only about 5% of cases of coronary artery bypass grafting, and further advances were necessary to take minimally invasive cardiac surgery into the general cardiac domain. Port access coronary artery bypass lends itself to triple vessel disease, although sometimes a wider or second incision is necessary. Minimally invasive direct coronary artery bypass is not currently practicable, especially for areas on the back of the heart. Building on their experience with the use of stabilisers, however, surgeons have gone back to the median sternotomy but can now perform all the necessary grafts without cardiopulmonary bypass (off pump coronary artery bypass). The level of skill needed by the cardiac surgeon is high, but the benefits from lower morbidity are immense. The“beating heart” technique holds tremendous promise for patients.

The arguments still continue over whether more damage comes from the
sternotomy or from the cardiopulmonary bypass. Trials are needed to validate the different techniques . Meanwhile, off pump coronary artery bypass (beating heart) will increasingly dominate for the next few years, accounting perhaps for half of all coronary artery bypass graft operations soon, but port access coronary artery bypass may yet resurface as its costs come down and its technology and ease of use improve.
Brian Glenville, MS FRCS Consultant cardiothoracic surgeon.

G-Test , A new test of Ovarial Function

By: Paul Serhal et.al.
The Assisted Conception Unit
University College Hospital, London

PATIENT INFORMATION

Female fecundity is generally acknowledged to decrease with increasing age and the fall in fecundity starts by the age of 30 years. However fecundity is not only correlated with chronological age but with the state of the ovarian reserve. The decline in the fertility potential is related to a process of egg depletion and diminished egg quality, factors referred to as ovarian reserve. It is this potential that declines with age and initially this decline may manifest itself in subtle ways, such as low fecundity rates and longer mean durations for women to conceive.

The most important aspect of diminished ovarian reserve, and the associated decline in reproductive potential, is that its onset in highly variable. Ovarian function is unique for each individual, both in the number of years of peak reproductive performance as well as in the onset and progression of its decline. Some women with normal menstrual cycles will have difficulty conceiving in their late twenties or early thirties. An important aspect of this group of patients is that they usually have normal regular menstrual cycles with serum progesterone levels in the luteal phase within the ovulatory range.

Until now it has not been possible to define how far individual patients have progressed through the process of depleting their ovarian reserve. Traditionally gynaecologists have relied on a single parameter to assess the ovarian reserve which is a measure of the basal FSH levels in the blood in the early follicular phase (Cycle Days 2 - 5). However women with baseline values in the normal range may indeed have diminished reserves and by the time an elevation in the FSH level is evident it is probably too late for them to achieve a pregnancy or have fertility treatment.
Some women with a normal FSH can be totally unaware that their ovarian reserve is steadily declining and are lulled into a false sense of security with regard to their prospects of starting a family.

The GnRH analogue test (G-Test) has been developed at The Assisted Conception Unit at University College Hospital. It is a new dynamic test of ovarian function, the purpose of which is to challenge the ovaries during Days 2, 3 and 4 of the menstrual cycle. Stimulation is achieved with a GnRH analogue in the form of a nasal spray. Blood samples are also taken on Days 2, 3 and 4. A baseline FSH/LH and oestradiol level is taken on Day 2 and the pattern of the response plotted on a graph which clearly shows the line of response. Consequently the results can be categorised into a good, sub-optimal or poor response.

This test is now applied clinically at our Unit as a:

• guide for determining the optimal dose of fertility drugs for women undergoing IVF treatment. IVF Units usually rely on the patient's age as the only index for specifying the quantity of fertility drugs to be taken which is hardly scientific. The G-Test is now performed in our Unit on all patients prior to undergoing IVF treatment in order to:
  

1. Predict the exact dosage for each individual patient
2. Identify poor responders and therefore reduce cancellation rate
3. Identify excessive responders and therefore reduce the risk of hyperstimulation

• For women with a sub-optimal result it is important for them to know that they are not necessarily infertile, however adjustments may have to be made to their ovarian stimulation regime to compensate for a diminished ovarian reserve.
• as a prognostic factor for the treatment of infertile couples

We consider that this test is indicated for all infertile women and for those with a family history of early menopause. It is not however intended to be used as a guide when deciding whether or not to delay starting a family for women over the age of 35 years. There is a natural decline of fertility in women and even with a normal G-test result we strongly recommend starting a family sooner rather than later. The G-Test is only used in women over the age of 35 years as a means to ascertain whether assisted conception would be of benefit should spontaneous conception fail to occur.

Mr. Khaldoun Sharif M.D., M.R.C.O.G., M.F.F.P.
Consultant Obstetrician and Gynaecologist,
Director of Assisted Conception Services,
Birmingham Womens Hospital,

Infertility is a common condition affecting 1 in 6 couples. The commonest cause, present in about 50% of cases, is male factor. Developments in the 80s and the early 90s, mainly in vitro fertilisation (IVF) and sperm injection techniques, led to high chances of successful treatment in many infertile men, even those with very low sperm count. Nevertheless, there remained a significant proportion (about 10%) of infertile men who have no sperm in the ejaculate (azoospermia) and hence could not be offered assisted conception. However, over the past 5 years significant advances have occurred, and we can now offer highly successful fertility treatment to azoospermic men. In this article we will review the causes of azoospermia, the available treatments, and the impact of these recent advances.

Traditional treatment:

Azoospermia could be either obstructive (40%) or non-obstructive (60%).

In obstructive azoospermia spermatogenesis is not impaired but there is genital tract obstruction. It could be congenital or acquired secondary to previous infection or surgery. Surgical obstruction could have been accidental (e.g. hernia repair) or intended (vasectomy).

Until recently the only available treatment was microsurgery. In post-surgical obstruction, surgery offers 20-60% chances of pregnancy and in post-infection obstruction it offers 30-40%. This meant that almost half of those with acquired obstructive azoospermia had poor surgical prognosis. In addition, congenital cases are not surgically treatable.

In non-obstructive azoospermia spermatogenesis is impaired, and clinically there is small size testes. Non-obstructive azoospermia is classified according to the serum level of gonadotrophins, mainly FSH, into hypogonadotrophic (low FSH) and hypergonadotrophic (raised FSH) ­

The so called primary testicular failure. Hypogonadotrophic azoospermia is treated successfully with hormone replacement, but it is responsible for less than 5% of cases.

The great majority of patients with non-obstructive azoospermia have primary testicular failure, and there is no medical or surgical treatment to reverse the condition. Until recently, there was no chance for these men fathering children.

So traditionally, more than 75% of azoospermic men had no hope of successful treatment.

New advances in male infertility have come about recently, and will be published in the News section of Doctorinternet web site.

ORAL SILDENAFIL IN MEN WITH ERECTILE DYSFUNCTION:
GENERAL UROLOGICAL PRACTICE EXPERIENCE.

Mohamed Hammadeh,
John Hines, Anthony Hirsh, AND Timothy Philip.
Department of Urology, Whipps Cross Hospital, London, UK

INTRODUCTION: Recently, oral Sildenafil (Viagraâ) has been introduced as an effective oral treatment for male erectile dysfunction (ED). We performed a prospective study to evaluate the efficacy and safety of oral Sildenafil in a busy general district hospital.
PATIENTS AND METHODS: 102 consecutive patients (mean age 55.6 years, range: 21-75) underwent baseline IIEF questionnaire (questions 3,4 and 14)(with their partners), physical examination, hormone profile, and the cause of their ED was identified. The patient was initially given 4 tablets (50 mg) to use at home with the instructions to increase or decrease the dose to 100 mg or 25 mg depends on the response and reviewed after one month. The patients who had good results were reviewed at 3 and 6 months.
RESULTS: The mean duration of ED was 37.3 months (6-120). The common causes of ED were psychological 35%, mixed 33%, diabetes 14%, surgery 6%, vascular 4%, and others 10%. 78 patients (76%) had good erections sufficient for penetration, which were maintained at 3 months in 76 patients (93%). 5 patients (5%) had poor response, 2 patients (2%) initially had good response, which was not maintained and 17 patients (17%) unevaluated to date. Side effects were flushing 7% (6 patients), headache 6% (5 patients), and rhinitis 1% (1 patient).
CONCLUSION: Oral Sildenafil (Viagraâ) significantly improved the quality of erection and sexual satisfaction in the majority of our unselected patients.

ADVANCES IN THE MANAGEMENT OF INFERTILITY:
OUT-PATIENT MANAGEMENT OF TUBAL DISEASE

Mr. Khaldoun Sharif MRCOG, MFFP, MD
Consultant Obstetrician & Gynaecologist
Director of Assisted Conception Services
Birmingham Women¹s Hospital

I ntroduction
Infertility is a distressing and common problem, affecting 1 in 6 couples. Tubal disease is found in 33% of infertile couples. In about 10­25% of these there is proximal tubal occlusion (PTO), occurring at the utero-tubal junction. The conventional treatment for infertility due to PTO is either tubal microsurgery or in-vitro fertilisation (IVF). Although both these treatment modalities are associated with good success rate, never-the-less,they are invasive, expensive and require either major surgery or the administration of drugs over a number of weeks. More recently, selective salpingography and guide-wire cannulation Have been used as minimally invasive, out-patient procedures for the assessment and successful treatment of PTO.

Background
Initially it was thought that PTO was always due to irreversible obliterative fibrosis that could not be overcome, but had to be resected (by surgery) or by-passed (by IVF). However, pathological studies of proximal tubal segments ­ surgically excised for the treatment of PTO ­ showed that 61% of patients had amorphous material/ mucus plugs or only minimal inflammation. This was despite pre-operative laparoscopy and hysterosalpingography (HSG), both confirming PTO. This seemingly false positive PTO indicated the need for the development of further investigations, and these were found to be not only diagnostic but also of therapeutic value in most cases. 

Selective salpingography & guide wire cannulation Selective salpingography is performed by the abutment of a cannula against the intrauterine ostia (without entry into the tubal lumen) and the use of a radio-opaque dye as in HSG. The cannula is introduced through the cervix and manipulated into position under fluoroscopic control. This is done as an out-patient procedure under local anaesthesia. In 10-33% of cases of PTO, selective salpingography alone leads to tubal patency. Otherwise, a special guide wire is introduced through the cannula into the tubal lumen in order to Œrecanalises¹ the tube (figure).

Results
Overall, the tubal patency rate (as demonstrated by subsequent HSG) following selective salpingography and guide wire cannulation is between 80 to 90%. In these patients, the subsequent pregnancy rate is about 35%, the majority occurring during the first 6 months. In cases where patency is not achieved, or the patient did not become pregnant within 6-12 months, tubal surgery or IVF could be offered. The results of these treatment are not compromised by the prior performance of selective salpingography.

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