Italy bans unvaccinated children from school


  A generic photograph of a vaccine being drawn from a vial into a needle
The new law demands 10 compulsory vaccinations – and has proved controversial

Italian children have been told not to turn up to school unless they can prove they have been properly vaccinated.

The deadline follows months of national debate over compulsory vaccination.

Parents risk being fined up to €500 (£425; $560) if they send their unvaccinated children to school. Children under six can be turned away.

The new law came amid a surge in measles cases – but Italian officials say vaccination rates have improved since it was introduced.

Under Italy’s so-called Lorenzin law – named after the former health minister who introduced it – children must receive a range of mandatory immunisations before attending school. They include vaccinations for chickenpox, polio, measles, mumps, and rubella.

Children up to the age of six years will be excluded from nursery and kindergarten without proof of vaccination under the new rules.

Those aged between six and 16 cannot be banned from attending school, but their parents face fines if they do not complete the mandatory course of immunisations.

The deadline for certification was due to be 10 March after a previous delay – but as it fell on a weekend, it was extended to Monday.

“Now everyone has had time to catch up,” Health Minister Giulia Grillo told La Repubblica newspaper.

She had reportedly resisted political pressure from deputy prime minister Matteo Salvini to extend the deadline even further.

Ms Grillo said the rules were now simple: “No vaccine, no school”.

Italian media report that regional authorities are handling the situation in a number of different ways.

In Bologna, the local authority has sent letters of suspension to the parents of some 300 children, and a total of 5,000 children do not have their vaccine documentation up to date.

In other areas there have been no reported cases, while still others have been given a grace period of a few days beyond the deadline.

Is the law having an effect?

The new law was passed to raise Italy’s plummeting vaccination rates from below 80% to the World Health Organisation’s 95% target.

On Monday – the last day for parents to provide documentation proving their children had been properly vaccinated – the Italian health authority released figures claiming a national immunisation rate at or very close to 95% for children born in 2015, depending on which vaccine was being discussed.

The 95% threshold is the point at which “herd immunity” kicks in – when enough of the population is vaccinated for the spread of the disease to become unlikely, thereby protecting those who cannot be vaccinated.

That includes babies too young to be vaccinated themselves, or those with medical conditions such as a compromised immune system.

Last month, an eight-year-old recovering from cancer was unable to attend school in Rome due to his weak immune system.

The child had spent months receiving treatment for leukaemia, but was at risk of infection because a proportion of pupils in the school had not been vaccinated – including several in the same class.

Image copyright Getty Images
Image caption Demonstrations against compulsory vaccination were held in Rome, 2017

The Lorenzin law, drafted by the previous government, had a tumultuous birth. When the current coalition came to power, it said it would drop mandatory immunisations although it later reversed its position.

The two populist parties in power had faced accusations that they were pursuing anti-vaccination policies.

Writing in a Facebook post on Monday, Ms Grillo admitted it “is a law that, at the time of approval, we criticised for several reasons” – and said that the law would be changed to include only those vaccinations that were necessary based on scientific data.

Why do parents not immunise their children?

The anti-vaccination movement has been growing globally in recent years, sparking alarm from the World Health Organization.

A long-discredited paper by Andrew Wakefield was behind much of the scare, but rumours around immunisation have continued to spread, leading to public health risks as not enough people are immune to such diseases.

Mr Wakefield was struck off the UK medical register after fraudulently claiming there was a link between the measles, mumps and rubella vaccine (MMR) and autism and bowel disease in children.

He made the claim based on the experiences of just 12 children, and no other study since has been able to replicate his results.

Italy proposal to jail vegans who impose diet on children


A woman, wearing a shirt reading "proud to be vegan", carries a vegan hamburger during the Vegan Fest fair on 13 October 2014 in the Israeli city of Ramat Gan near Tel Aviv
A growing fashion for veganism is putting children at risk, according to the bill’s supporters

Parents who restrict their children to a vegan diet could face a jail term if a controversial bill is passed by the Italian parliament.

Such parents, the draft bill claims, are imposing a diet “devoid of essential elements for [children’s] healthy and balanced growth”.

It has been proposed by Elvira Savino of the centre-right Forza Italia party.

It follows a number of high-profile Italian cases where malnourished children have been taken into care.

In four cases over the last 18 months, malnourished children were hospitalised in Italy after being fed a vegan diet.

However, dieticians such as the American Dietetic Association say vegan diets are suitable for children but advise that care needs to be taken to ensure children are receiving the full range of required nutrients – in particular vitamin B12.

Doctors speculated in some cases that the guardians of the hospitalised children may not have understood how to supplement a vegan diet to make it safe for children.

What is veganism?

A vegan diet eliminates anything which originates from animals:

  • No meat, fish, animal fats or gelatine
  • No dairy products such as cow’s milk, cheese, butter, yogurt, goat’s or sheep’s milk
  • No eggs nor foods containing eggs such as Quorn
  • No honey

 


Serb woman holds milk and eggs

Ms Savino’s proposed bill will be discussed by parliamentary committees before going to the chamber for debate – probably later this year, reports Reuters news agency.

Meanwhile, three rival bills are on the table – all aiming to make vegan and vegetarian options more commonplace in Italian canteens.

‘Reckless and dangerous’

In the preamble of Ms Savino’s bill (in Italian), she highlights the spreading belief in Italy of “substantial health benefits” provided by a vegetarian or vegan diet.

“There is no objection if the person making this choice is an informed adult. The problem arises when children are involved… The vegetarian or vegan diet is, in fact, deficient in zinc, iron, vitamin D, vitamin B12 and omega-3”.

Her draft bill aims to “stigmatise the reckless and dangerous eating behaviour imposed by parents” who pursue a vegan diet, “to the detriment of minors”.

Offenders would face up to a year in jail – rising to a maximum of four years where the child suffers illness or permanent injury and six years in the case of death.

While some nutrition experts have challenged the validity of the bill, other commentators have cautioned that its imprecise wording means it could be used to penalise a far greater range of parents than vegans or vegetarians – for instance, the parents of obese children.

Some say better public health education rather than punitive measures would be more effective at improving children’s nutrition.

Licorice overload may cause seizures


Overconsumption of candies with licorice is associated with tonic clonic-seizures and hypertension in a case study.

The report involved a 10-year-old boy who was admitted to a hospital in Bologna, Italy following generalized tonic-clonic seizures. The boy had an elevated blood pressure. A brain magnetic resonance scan showed a localized vasogenic oedema. [Pediatric Neurology 2015;52:457-459

A follow-up examination offered the clue:  the boy’s teeth had black stains.  He later admitted to have consumed 20 licorice toffees per day in the past 4 months. This amounts to 2.88 mg/kg of glycyrrhizic acid, which gives licorice its sweet taste, and exceeds the WHO’s maximum recommendation of 2 mg/kg. This partly explained the reason for his hypertension, said the authors.

The risk of seizures from licorice is of particular concern in children with low body weight, they added. Licorice consumption is also linked to posterior reversible encephalopathy syndrome in children.

 

Why do some people prefer bitter drinks?


There’s been a wave of popularity for drinks like the Aperol spritz, the Negroni, and a host of cocktails flavoured with “bitters”. Why are people turning their backs on sweet cocktails in favour of a bitter taste?

The last two decades have seen an extraordinary resurgence in cocktail-making on both sides of the Atlantic, with everything from Cointreau-sweetened Cosmopolitans to sugary Mojitos being drunk in vast quantities.

But there is now a definite trend towards bitter drinks. People are ordering whisky or gin-based drinks paired with vermouths. And there is growing interest in the US, UK and other European nations in Italian amari.

These complex, herbal, bittersweet drinks, with names like Averna, Ramazzotti, Montenegro and Fernet Branca, are usually consumed as aperitivi or digestivi – drinks thought to either encourage the appetite before dinner or help with digestion afterwards.

Bitter tasting cocktails are having a renaissance

Their bitter mixer cousins, Cynar, Campari and Aperol, are increasingly being used in cocktails.

Aperol – based on bitter orange and rhubarb and containing classic bitter ingredients like gentian and cinchona (a source of quinine) – has rocketed in popularity in recent years following a push by owner Gruppo Campari.

Old fashioned cocktails

Sales rose 156% in the UK in 2012 and 56% in the US. This year’s figures, announced soon, are expected to be even bigger. A poster campaign in the UK encourages people to try an Aperol spritz – prosecco sparkling wine and soda water mixed with Aperol.

A fundamental point of the spritz is its low alcohol content. Aperol’s slogan is “poco alcolico”, roughly meaning a little bit alcoholic.

“I think the Aperol spritz was probably the most asked-for drink in the outdoor areas of most decent bars in London this summer,” says World Duty Free mixologist Charlie McCarthy.

Laura Tallo, from Nonna’s Italian Cucina in Bath, says many British drinkers have returned after holidays in Italy, having seen certain drinks paired with tavola calda – the selection of hot, freshly-baked food.

“People are definitely beginning to embrace the Italian custom of drinking aperitifs. We have seen a definite trend emerging of people choosing classic Italian pre-dinner drinks such as an Aperol spritz, Negroni [equal parts Campari, gin and sweet vermouth], Americano or Martini,” she says.

The expert viewBrooklyn-based author Brad Thomas Parsons, wrote Bitters: A Spirited History of a Classic Cure-All:”Bitters, as a term, is more like an umbrella for a variety of liquid seasonings. From citrus to aromatic to floral and beyond. There should be a bittering agent to be a proper bitters but bitters are concentrated and not meant to be consumed on their own.”Amaro, on the other hand-potable spirits like Cynar, Fernet, and Averna-are meant to be imbibed on their own (or as an ingredient in a drink). These are definitely bitter to the taste-ranging from the soft end of bittersweet to bracingly medicinal.”

Such drinks are not to everyone’s taste, of course. While many Italians have been brought up around the tradition of amari, they can baffle non-Italian palates at first taste.

“They say of a Negroni the first two or three sips you despise, and after you have had two or three drinks you start to like it,” says Tom Ross, bars manager of the Polpo restaurant group in London.

The taste of Fernet Branca – vaguely minty but with pungent undertones of cough medicine – is so powerful that comedian Bill Cosby constructed a seven-minute anecdote around his initial horror on encountering the drink in Italy. And yet Fernet is loved by many, being drunk with cola in Argentina and – accompanied by a separate shot of ginger beer – known as the “bartender’s handshake” in San Francisco.

One of the first recorded definitions of a cocktail was in a New York journal in 1803, which classified it as a mixture of any “spirituous liquor”, with water, sugar and “bitters”, known at the time as a bittered sling.

bartender pouring bitters

You can find the descendant of these traditional bitters (with the term typically referring to both singular and plural) in any decent bar in the UK or US. There’ll be a rather unusual bottle among the others – small with a yellow top and an oversized label covered in small print. It is the world’s most famous cocktail bitters, Angostura.

A matter of taste.

Tongue
  • Humans can detect five basic tastes – sweet, sour, bitter, salty and umami (savoury); some evidence that fat may be sixth taste
  • Bitter tastes include coffee, beer, unsweetened cocoa and citrus peel
  • Sour is indicative of acidity; taste found in citrus fruit, wine, and sour milk

This bitters is the key ingredient in pink gin, the traditional officers’ cocktail in the Royal Navy. It’s also the bedrock of famous cocktails, including the Old Fashioned, beloved of Mad Men’s Don Draper, and the Manhattan. A supply shortage in 2009 caused panic throughout the world’s bartending community, according to McCarthy, and prompted bartenders to start making their own.

The current wave of speakeasy-type bars inspired by the prohibition years in the US, has prompted interest in traditional and hitherto forgotten cocktails. This in turn has prompted demand for more unusual bitters.

Bob Petrie, of Bob’s Bitters, started in 2005 when he was approached by the Dorchester Hotel to create a range.

Traditional bitters are very complex, with aromatic flavours brought out from a combination of barks, roots, herbs, and spices by macerating them in alcohol. He looked at pairing them with the “botanicals” in gin, and came up with a range including cardamom, chocolate, coriander, ginger, grapefruit, lavender, liquorice, orange and mandarin, peppermint and vanilla.

“Single flavours are a lot easier for the barman as it gives a lot more scope,” Petrie says.

bitter bottles

“What they can do with mine is mix and match.”

Rochdale-born US celebrity mixologist Gary Regan is another who was prompted to make his own to replicate the orange bitters in some old cocktail recipes.

“When I realised it was hard to get good ones I decided to make my own. I stole a recipe from the Gentleman’s Companion of 1939. I had about four different trials and eventually got something I liked.

Bitter history.

Angostura bark
  • Prepared by infusion or distillation, using ingredients such as angostura bark (pictured), cascarilla, cassia, gentian, orange peel, and quinine
  • Angostura bitters first sold in 1824 as cure for sea sickness and stomach maladies, named after Venezuelan town where it was formulated
  • Quinine derived from cinchona tree bark; used as treatment for malaria, lupus and arthritis and in very dilute form in tonic water and bitter lemon

“This shift towards bitter has been going on for eight years,” Regan estimates. “[But] most bitters aren’t that bitter. They taste herbal. In fact, they are a bit on the sweet side sometimes.”

Fee Brothers in Rochester, New York, has been making bitters since 1863, with a short break for prohibition. Joe and Ellen Fee are the fourth generation. Their 92-year-old father still regularly visits the plant.

Joe Fee says there has been a marked increase in sales over the past seven years. “Just about anything can be made into a bitters. They are your spice rack behind the bar.”

“I am the Willy Wonka of the cocktail mixers,” boasts Ellen Fee, who conjures up the new flavours. “I like to think in terms of what flavour is already bitter. Cocoa powder is bitter, cranberry is bitter. You add to that and make it more interesting.”

The plethora of these cocktail tinctures and potions shows the tastes of aficionados have shifted. But there are other flagbearers for a more bitter palate.

Many James Bond fans attempt to recreate the Vesper Martini from Casino Royale. Bond asks for it to be made with strong gin, vodka and the bitter Kina Lillet. Lillet took out much of the bitter quinine in the 1980s and fans tend to use Cocchi Americano Italian vermouth instead.

And the Queen has followed in her mother’s footsteps by drinking gin and Dubonnet – the quinine-bittered French aperitif. Just a few years ago, her choice was seen as unusual.

Now she’s part of an established trend.

Rituximab outperformed steroids in Graves’ ophthalmopathy.


Despite data presented earlier at the American Thyroid Association Annual Meeting showing that rituximab was not effective in treating Graves’ ophthalmopathy, another presenter here said that the drug does improve disease state when compared with methylprednisolone.

“Response to rituximab was as high as 93%, compared to 69% observed after IV steroid,”Mario Salvi, MD, from the University of Milan in Italy, said. “Preliminary evidence of NOSPECS class 2 signs shows improvement after rituximab.”

Similar to the study presented earlier at the meeting, Salvi said the primary endpoint was a change of two or more points in the clinical activity score (CAS) at 24 weeks. Secondary endpoint was a reduction of disease severity by at least two NOSPECS classes.

Inclusion criteria included euthyroid for at least 6 to 8 weeks and affected by active Graves’ ophthalmopathy. Any previous steroid treatments had to be stopped at least 3 months before study inclusion.

Patients were randomly assigned to IV methylprednisolone (n=16; mean age, 50.4 years) or rituximab (Rituxan, Genentech; n=16; mean age, 51.9 years). In both groups, six patients had received previous steroid treatment. Originally, Salvi said, patients in the rituximab group were receiving 1,000 mg in two doses, but after two adverse reactions, they lowered the dosage to 500 mg. There was no difference between these two treatment dosages at 24 weeks.

At 12 weeks, the difference between the two groups was not significant, but at 24 weeks, 93% of patients in the rituximab group improved, as compared with 69% of the steroid group (P<.02).

“Rituximab was more effective than IV methyprednisolone in inactivating Graves’ orbitopathy, as assessed at 24 weeks,” Salvi said. “Graves’ orbitopathy remained invariably inactive after rituximab during follow-up.”

The researchers are confident in the response seen from methylprednisolone as it is as high as seen in recently published studies, Salvi said.

These results were preliminary and final analysis is expected shortly, he added.

PERSPECTIVE

 

Kenneth D. Burman

·         Both of the studies and each of the investigators did an excellent job in performing their studies. These studies are complex as it is difficult to recruit patients and to monitor them closely.

My initial impression is that the studies were designed differently. The Mayo Clinic study had rituximab as the active agent vs. placebo as the control, whereas the Italian study had rituximab as the active agent vs. intravenous steroids as an active control.

The doses of rituximab were also different. Salvi reduced the dose of rituximab mid-study and the lower dose was 500 mg/day vs. a total of 2,000 mg/day earlier in the study; the Mayo Clinic study used 2,000 mg. Salvi, et al suggested the lower dose was equally efficacious, but this needs to be explored further.

The major controversy relates to the patient population studied and whether the patients had received previous therapy, how recently this therapy had been given, the extent of therapy and the duration of disease. Stan, et al noted that about two-thirds of their patients did not receive treatment prior to the rituximab treatment, while Salvi, et al noted that six patients in each arm of their study had steroid treatment, but not within 3 months of the study.

Salvi, et al did indicate that their patients had progressive disease, which can defined by various scales. The CAS score, which was the sole measure in Salvi’s study, takes into account a multitude of factors. Stan, et al asserted that 24 of his 25 patients were classified as progressive as well. If the disease is progressive and treated early, the effect of immunomudulatory treatment is expected to be more efficacious. It is difficult to know with certainty if both studies analyzed patients at similar time points in the progression of ophthalmopathy.

Rituximab is not approved by the FDA for the treatment of Graves’ ophthalmopathy, The question now arises whether rituximab is effective in the treatment of progressive Graves’ ophthalmopathy given the apparent different results in these two clinical trials. Perhaps, the most appropriate advice is to refer these patients to large, tertiary medical centers that have extensive experience in treating patients with progressive Graves’ ophthalmopathy. Given that most physicians treating Graves’ ophthalmopathy are not experienced with using rituximab, and also give these conflicting results, it seems most prudent to not advise individual physicians to consider using rituximab therapy in this context outside of a tertiary medical center or a clinical trial.

o    Kenneth D. Burman, MD

o    Chief of the Endocrine Section at Washington Hospital Center 
Professor of Medicine 
Georgetown University

 Soure: Endocrine Today

Esmolol May Stabilize Heart Rate in Septic Shock Patients.


For patients in septic shock who have an excessively high heartbeat, use of the beta blocker esmolol helped to lower and maintain heartbeat rates without adverse effects.

Andrea Morelli, MD, from the Department of Anesthesiology and Intensive Care, University of Rome, “La Sapienza,” Italy, and colleagues conducted a randomized phase 2 trial at the University of Rome hospital intensive care unit between November 2010 and July 2012. The researchers randomly assigned 154 patients whose heartbeats exceeded 95 beats per minute (BPM) and who required high doses of norepinephrine to receive either continuous infusion of esmolol to maintain heart rate between 80 and 94 BPM (n = 77) or to receive standard treatment (n = 77) of norepinephrine during intensive care unit stays.

The target heartbeat rate was achieved in all patients in the esmolol group and was significantly lower than for patients in the control group. The median heart rate reduction came to −28 BPM for the esmolol group compared with −6 BPM for the control group (P < .001). The median continuously infused dose for esmolol was 100 mg/h (interquartile range [IQR], 50 – 300 mg/h).

The mortality rate for the esmolol group came to 49.4% for the esmolol group compared with 80.5% for the control group (P < .001). Stroke volume index was significantly higher in the esmolol group (P = .02), as was the left ventricular stroke work index (P = .03). Fluid requirements were reduced in the esmolol group compared with controls (P < .001), although no clinically relevant differences existed between groups for some other cardiopulmonary variables.

“Compared with standard treatment, esmolol also increased stroke volume, maintained [mean arterial pressure], and reduced norepinephrine requirements without increasing the need of inotropic support or causing adverse effects on organ function,” the researchers write.

Because esmolol is short-acting and has a half-life of about 2 minutes, it enables rapid resolution of any potential adverse effects. These new findings, the researchers write, suggest esmolol “allows better ventricular filling during diastole, hence, improving stroke volume and thereby improving the efficiency of myocardial work and oxygen consumption.”

Limitations of the study include selection of a predefined arbitrary heart rate threshold and the requirement that the study be nonblinded and not placebo-controlled. In addition, results might not be similar in a less at-risk population.

Paves the Way

“This is the unblindable trial. There’s no way to blind this trial. That will always be a limitation of whatever comes down the road,” R. Phillip Dellinger, MD, professor and head of critical care medicine at Cooper University Hospital in Camden, New Jersey, told Medscape Medical News. Dr. Dellinger is first author of a recent articleon treatment guidelines for sepsis.

The new study, Dr. Dellinger said, “clears the way for a larger phase 3 trial, and it offers support for moving the physiology in the direction that would, on the surface, look beneficial. It shows that it’s safe. The secondary outcomes all moved in a positive direction or didn’t move at all. So there are no signals here of potential problems with doing this; instead there is evidence that it helps cardiac function.”

Some aspects of this phase 2 trial differ from many phase 2 trials, he added. “This trial picked a population that would be predicted to more likely benefit from beta blockage, which is requiring very high doses of norepinephrine and being tachycardic.” Limiting the trial population may be better than including a large population in a study and dividing them up in subgroup analyses, he said, but the results might not be generalizable to a larger population.

In summary, Dr. Dellinger said, “Even though the trial was small, I think it was encouraging.”

This research was funded by the Department of Anesthesiology and Intensive Care of the University of Rome, “La Sapienza.” Dr. Morelli reports receiving honoraria for speaking at Baxter symposia. One coauthor reports serving as a consultant for and receiving honoraria from speaking at Baxter. The other authors and Dr. Dellinger have disclosed no relevant financial relationships.

Confirmed by science: You really can change your DNA – and here’s how.


If you believe that you are at the mercy of your genetic code, great news, you’re not. According to the science of epigenetics (the study of how environmental factors outside of DNA influence changes in gene expression), stem cells and even DNA can be altered through magnetic fields, heart coherence, positive mental states and intention. Top scientists around the world agree: genetic determinism is a flawed theory.

Dna-2

Curbing the genetic victim mentality

The DNA we are born with is not the sole determinant for our health and well-being. Stem cell biologist Bruce Lipton, Ph.D., discusses the important difference between genetic determinism and epigenetics in an interview with SuperConsciousness magazine:

“The difference between these two is significant because this fundamental belief called genetic determinism literally means that our lives, which are defined as our physical, physiological and emotional behavioral traits, are controlled by the genetic code. This kind of belief system provides a visual picture of people being victims: If the genes control our life function, then our lives are being controlled by things outside of our ability to change them. This leads to victimization that the illnesses and diseases that run in families are propagated through the passing of genes associated with those attributes. Laboratory evidence shows this is not true.”

Lipton’s theory is confirmed by Carlo Ventura, M.D., Ph.D., professor and researcher at the University of Bologna in Italy. Dr. Ventura has shown through lab testing that the DNA of stem cells can be altered using magnetic field frequencies.

“It’s like a time machine. You’re reprogramming somehow backward with these cells to an uncertain state in which any kind of decision is somehow possible; even the decision to become virtually any kind of cell of the organism. And just think about the tremendous potential of this discovery.”

He adds that two Nobel Prize-winning scientists discovered even “nonstem adult cells can be epigenetically reprogrammed backward to a state where they can eventually give rise to neural cells, cardiac cells, skeletal muscle cells or insulin-producing cells.”

Changing DNA through intention

According to the Institute of HeartMath in Boulder Creek, California, epigenetics encompasses far more than just DNA, our environment and life experience. After two decades of study, the researchers discovered factors like love and appreciation or anxiety and anger also influence a person’s blueprint. In one experiment, select participants were able to change DNA with positive mental states.

“An individual holding three DNA samples was directed to generate heart coherence – a beneficial state of mental, emotional and physical balance and harmony – with the aid of a HeartMath technique that utilizes heart breathing and intentional positive emotions. The individual succeeded, as instructed, to intentionally and simultaneously unwind two of the DNA samples to different extents and leave the third unchanged.”

Control group volunteers who had low heart coherence were unable to alter the DNA.

Healthy cell expression and a quantum nutrient diet

If we want to nourish our bodies at a cellular level (and not promote disease), the institute recommends an abundant diet of quantum nutrients. When we are stressed or negative, our biological energy reserves are diverted from the important task of regenerating and repairing the body. We can counteract this cellular starvation by focusing on genuine states of care, appreciation and love. These positive emotions enhance our energy system and feed the body, even down to the level of DNA. HeartMath calls such positive feelings “quantum nutrients.”

The institute offers several free tools that assist in creating a coherent state quickly and easily. Two examples can be found here and here.

Sources:

http://www.heartmath.org

http://www.superconsciousness.com

http://www.heartmath.org

http://www.heartmath.org

http://item-bioenergy.com

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.


Background
Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis.
Methods
We did a multicentre trial in two phases. We enrolled patients aged 5—30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3—6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551.
Findings
We screened 540 patients and enrolled 171 (mean age 13•8 years, SD 5•9, range 5—30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16•3% in the alendronate group (n=65) versus 3•1% in the placebo group (n=63; p=0•0010). 19 of 57 young people (33•3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events.
Interpretation
Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density.
Source: Lancet

Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial.


Background

Effective reduction of albuminuria and blood pressure in patients with type 2 diabetes who have nephropathy is seldom achieved with available treatments. We tested the effects of treatment of such patients with daglutril, a combined endothelin-converting enzyme and neutral endopeptidase inhibitor.

Methods

We did this randomised, crossover trial in two hospitals in Italy. Eligibility criteria were: age 18 years or older, urinary albumin excretion 20—999 μg/min, systolic blood pressure (BP) less than 140 mm Hg, and diastolic BP less than 90 mm Hg. Patients were randomly assigned (1:1) with a computer-generated randomised sequence to receive either daglutril (300 mg/day) then placebo for 8 weeks each or vice versa, with a 4-week washout period. Patients also took losartan throughout. Participants and investigators were masked to treatment allocation. The primary endpoint was 24-h urinary albumin excretion in the intention-to-treat population. Secondary endpoints were median office and ambulatory (24 h, daytime, and night-time) BP, renal haemodynamics and sieving function, and metabolic and laboratory test results. This study is registered with ClinicalTrials.gov, number NCT00160225.

Findings

We screened 58 patients, of whom 45 were enrolled (22 assigned to daglutril then placebo, 23 to placebo then daglutril; enrolment from May, 2005, to December, 2006) and 42 (20 vs 22) were included in the primary analysis. Daglutril did not significantly affect 24-h urinary albumin excretion compared with placebo (difference in change −7·6 μg/min, IQR −78·7 to 19·0; p=0·559). 34 patients had complete 24-h BP readings; compared with placebo, daglutril significantly reduced 24-h systolic (difference −5·2 mm Hg, SD 9·4; p=0·0013), diastolic (—2·5, 6·2; p=0·015), pulse (—3·0, 6·3; p=0·019), and mean (—3·1, 6·2; p=0·003) BP, as well as all night-time BP readings and daytime systolic, pulse, and mean BP, but not diastolic BP. Compared with placebo, daglutril also significantly reduced office systolic BP (—5·4, 15·4; p=0·028), but not diastolic (—1·8, 9·9; p=0·245), pulse (—3·1, 10·6; p=0·210), or mean (—2·1, 10·4; p=0·205) BP, and increased big endothelin serum concentration. Other secondary outcomes did not differ significantly between treatment periods. Three patients taking placebo and six patients taking daglutril had mild treatment-related adverse events—the most common was facial or peripheral oedema (in four patients taking daglutril).

Interpretation

Daglutril improved control of BP in hypertensive patients with type 2 diabetes and nephropathy and had an acceptable safety profile. Combined endothelin-converting enzyme and neutral endopeptidase inhibition could provide a new approach to hypertension in this high-risk population.

Discussion

8-week treatment with daglutril plus losartan and other antihypertensive drugs did not significantly affect urinary albumin excretion, nor renal haemodynamic measures or sieving function, but it did decrease ambulatory blood pressure in hypertensive patients with type 2 diabetes mellitus and albuminuria. Treatment was safe and well tolerated in all participants.

Because dietary salt intake and concomitant anti-hypertensive treatment were not systematically changed and 24-h urinary sodium excretion was stable during the study, we can reasonably exclude any confounding effect of intensified hypertension treatment or reduced sodium exposure. Moreover, we detected no substantial carry-over effect and the crossover design avoided confounding related to interpatient data heterogeneity. Thus, the reduction of blood pressure associated with daglutril seems to be a genuine treatment effect.

To the best of our knowledge, this study is the first randomised clinical trial reporting the beneficial effects of daglutril on arterial hypertension in patients with type 2 diabetes mellitus (panel). Hypertension affects most patients with diabetes and almost all of those with some renal involvement;13 systolic hypertension is almost always present. When combined with increased pulse pressure, it is almost always a result of increased vascular stiffness—a major risk factor for cardiovascular morbidity and mortality in this population.19 Systolic hypertension is often resistant to drug treatment,19 especially in patients with diabetes with renal involvement; in our study, systolic blood pressure averaged 140 mm Hg, despite background treatment with losartan, plus two or more antihypertensive drugs, and also a diuretic in most cases. This blood pressure exceeds the 130 mm Hg target that was recommended when the study was designed, but accords with the most recent guidelines,20 which recommend less stringent control of blood pressure in patients with diabetes.

Source: Lancet

 

Prognostic Importance of White Coat Hypertension: Two out of Three?.


 

 In a long-term, population-based study, mortality risk was significantly elevated only in patients with hypertension on one of two out-of-office measures.

Although white-coat hypertension (elevated blood pressure [BP] on office measurement with normal BP on out-of-office measurement) has been known for many years, its importance and role in management decisions remain unclear. In the PAMELA study, 2051 residents of a town in northern Italy underwent three different BP measurements: in an office, self-administered at home, and 24-hour ambulatory monitoring. Participants were characterized as having normotension (all 3 measures normal), sustained hypertension (all 3 measures elevated), or white-coat hypertension (elevated office measure and ≥1 normal out-of-office measures). The white-coat–hypertension group was subdivided into participants with normal values on both out-of-office measures (true white-coat hypertension) and those with an elevated value on one measure (partial white-coat hypertension).

During an average of 16 years of follow-up, rates of cardiovascular and all-cause mortality increased progressively and significantly from normotension to white-coat hypertension to sustained hypertension. Compared with normotensive participants, rates of cardiovascular and all-cause mortality were significantly increased in participants with sustained hypertension and those with partial white-coat hypertension, but not in those with true white-coat hypertension. Results were similar after excluding participants receiving antihypertensive treatment. In 750 patients without sustained hypertension at baseline who underwent repeat measurements at 10 years, the rate of sustained hypertension increased progressively and significantly from normotension to true white-coat hypertension to partial white-coat hypertension.

COMMENT

In this study, the mortality risk associated with true white-coat hypertension was similar to that associated with normal blood pressure, whereas the risk associated with partial white-coat hypertension was comparable to that associated with sustained hypertension. These findings suggest that three forms of BP measurement (1 in-office, 2 out-of-office) are better than two for risk assessment in patients with white-coat hypertension.