Beckwith-Wiedemann syndrome Hypoglossal nerve injury ... - MDC

Beckwith-Wiedemann syndrome
Hypoglossal nerve injury
Lingual carcinoma
Sarcoidosis
Vitamin B12 deficiency
Damage to the hypoglossal nucleus or hypoglossal nerve can cause denervation atrophy
of the tongue, as seen in this patient. The patient had undergone right-sided radical neck
dissection 7 years earlier for a malignant tumor of the right tonsil.

Young child with Beckwith-
Wiedemann syndrome.
Note the macroglossia,
prominent eyes, eyelid
nevus flammeus and
barely visible linear ear
creases.
Note the wasted left side of the
tongue and deviation to the left
suggesting a left lower motor
neurone lesion.

Thrombopoetin oder auch Thrombopoietin (Gen-Name: THPO) ist ein Hormon, das die Bildung und
Differenzierung der Blutplättchen-bildenden Zellen, der Megakaryozyten, stimuliert. Es ist im
Rahmen der Thrombopoese notwendig für die Produktion von Blutplättchen (Thrombozyten).
Mutationen im THPO-Gen können zu (seltener) erblicher Thrombozythämie führen. Thrombopoetin
wird in der Leber, der Niere, sowie in den Stromazellen des Knochenmarks gebildet. Es nimmt an
verschiedenen Stellen Einfluss auf den Ablauf der Hämatopoese und wirkt dabei als Cytokin.
Neben dem Einfluss auf Megakaryozyten und der einhergehenden Bildung der Thrombozyten wirkt
Thrombopoetin auf hämatopoetische Stammzellen.
Bei Eltrombopag handelt es sich um einen nicht-peptidischen, oral aktiven Thrombopoetin-
Rezeptor-Agonisten. Dieser Wirkstoff stimuliert die Proliferation und Differenzierung von
Megakaryozyten – den Vorläuferzellen der Thrombozyten (Blutplättchen) – was zu einer Erhöhung
der Blutplättchenkonzentration führt.
Die Resultate einer klinischen Phase-III-Studie zeigten, dass bei den 114 Probanden mit
idiopathischer thrombozytopenischer Purpura die tägliche, orale Gabe von 50 mg Eltrombopag zu
einem deutlichen Anstieg der Anzahl Blutplättchen führte. Bei 80 % der Patienten, die Eltrombopag
erhalten, treten Nebenwirkungen auf.
Dies sind hauptsächlich Kopfschmerzen,
gastrointestinale Störungen (z.B. Übelkeit, Durchfall,
Erbrechen), Schlaflosigkeit, Augentrockenheit und
Hautausschlag. Schwerwiegende Nebenwirkungen
wurden keine beobachtet. Die positiven Resultate
der Phase-II-Studien wurden 2007 bereits publiziert.

Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia
We conducted a phase 2 study involving patients with aplastic anemia that was refractory to
immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag
(Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of
50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of
12 weeks. Primary end points were clinically significant changes in blood counts or transfusion
independence. Patients with a response continued to receive eltrombopag.
The Venn diagrams show the numbers of patients with
unilineage, bilineage, and trilineage hematologic responses.
Patients with a response and their response pattern at 12
weeks are shown on the left. Patients who met the response
criteria at the most recent follow-up assessment are shown on
the right.

Treatment with
eltrombopag was
associated with
multilineage
clinical responses
in some patients
with refractory
severe aplastic
anemia.

Renale Clearance bezeichnet die Clearance durch die Nieren, d. h. die Entfernung einer
bestimmten exogenen oder endogenen Substanz aus dem Blut als spezifische Leistung der
Nieren und gibt das Plasmavolumen an, welches pro Zeiteinheit von der entsprechenden
Substanz befreit wird. So z. B. für die Kreatinin-Clearance:
Die einfache Version der Cockcroft-Gault-Formel hilft, die Kreatinin-Clearance [ml/min] zu
schätzen.
The Modification of Diet in Renal Disease (MDRD)
Study was the largest randomized clinical trial to
test the hypothesis that protein restriction slows the
progression of chronic renal disease. However, the
primary results published in 1994 were not
conclusive with regard to the efficacy of this
intervention.

Cystatin C (auch: CysC) ist ein körpereigenes Protein, das in der Nierendiagnostik zur
Bestimmung der glomerulären Filtrationsrate (GFR) verwendet wird.
Die Serum-Normalwerte beim Menschen liegen für beide Geschlechter zwischen 0,53 und 0,95
mg/l. Erhöhte Werte finden sich bei eingeschränkter glomerulärer Filtrationsrate (GFR).
Cystatin C ist Mitglied der Cystatin-Familie der Cysteinproteasen-Inhibitoren. Cystatin C wird
von den meisten kernhaltigen Zellen in relativ konstanter Rate produziert; die Produktion scheint
auch bei entzündlichen Prozessen und anderen pathologischen Zuständen gleich zu bleiben.
Seltene Mutationen im CST3-Gen können erbliche Amyloidose und Makuladegeneration
verursachen.
Bei nicht möglicher 24-stündiger Urinsammlung für eine renale Clearance-Bestimmung ist
Cystatin C im Serum eine Alternative zur Diagnostik von Störungen der glomerulären Filtration.
Durch die größere diagnostische Sensitivität als Kreatinin im Serum scheint es auch Aussagen
im „Kreatinin-blinden Bereich“ zuzulassen.
Kreatinin = 0,40 €
Cystatin C = 4,0 €

Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C
Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely
used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney
disease. Cystatin C is an alternative filtration marker for estimating GFR. Using cross-sectional
analyses, we developed estimating equations based on cystatin C alone and in combination with
creatinine in diverse populations totaling 5352 participants from 13 studies. These equations
were then validated in 1119 participants from 5 different studies in which GFR had been
measured. Cystatin and creatinine assays were traceable to primary reference materials. Bias
was assessed as the median of the difference between measured GFR and estimated GFR, and
precision was assessed as the interquartile range for the difference. Accuracy was assessed as
the root-mean-square error and as the percentage of estimates that differed by more than 30%
from the measured GFR (1–P30) or by more than 20% (1–P20). Confidence intervals were
calculated by means of bootstrap methods (2000 bootstraps). The significance of the differences
among equations was determined with the use of the signed-rank test for bias, the bootstrap
method for the interquartile range and root-mean-square error from the 2000 bootstrap samples,
and McNemar's test for 1–P30 and 1–P20.

A reduction in GFR to less than 60 ml per minute per 1.73 m2 for 3 months or longer is a diagnostic criterion
for chronic kidney disease and is associated with an increased risk of adverse outcomes, including death.
Bias with the new, combined creatinine–cystatin C equation and with the average of the new cystatin C
equation and the creatinine equation was similar to that with the individual creatinine and cystatin C
equations, but they had greater precision and accuracy and resulted in more accurate classification of
measured GFR as less than 60 ml per minute per 1.73 m2 — the threshold for the diagnosis of chronic kidney
disease. 3.6% of U.S. adults would be classified as having chronic kidney disease solely on the basis of a
creatinine-based GFR estimate of 45 to 59 ml per minute per 1.73 m 2 . Our data suggest that a strategy of
measuring cystatin C when the creatinine-based estimate is in this range and then reestimating GFR with the
use of both these markers could correctly reclassify a substantial proportion of such patients as not having
chronic kidney disease and not being at high risk. This more accurate classification would result in more
selective use of resources, such as tests for complications of chronic kidney disease, adjustment of
medication doses, and referrals to nephrologists.

Delirium ist ein akutes, schweres, prinzipiell reversibles, organisch bedingtes Psychosyndrom
mit Bewusstseinsstörung. Kennzeichnend für das Delirium ist neben der Bewusstseinsstörung
eine Störung der Aufmerksamkeit, der Wahrnehmung, des Denkens, der Kognition, des
Gedächtnisses, der Psychomotorik und der Emotionalität. Pathognomonisch ist eine deutliche
tageszeitliche Fluktuation der Symptome. Die akute psychische Störung hat entweder eine
organische Ursache, oder entsteht aufgrund von Drogenwirkung oder Drogenentzug.
Weitere Symptome sind Herabsetzung des abstrakten Denkvermögens, der Konzentration, ein
eingeschränktes Kurzzeitgedächtnis und Desorientierung: Ein Betroffener ist nicht richtig
orientiert, was Ort, Zeit, seine eigene Person oder Situation betreffen kann. Beim voll
ausgeprägten Delirium kommt noch eine Störung des Schlaf-Wach-Rhythmus hinzu. Weitere
Symptome, wie optische Halluzinationen, Wahnvorstellungen, motorische Unruhe und nestelnde
Bewegungen sowie affektive Störungen wie Depression, Angst aber auch Euphorie oder
Reizbarkeit und eine Agitation (krankhafte Unruhe) können auftreten. Der Beginn dieser akuten
Störung ist plötzlich, die Symptomatik schwankt jedoch im Tagesverlauf. Die zwei Prägnanztypen
sind hyperaktives und hypoaktives Delirium. Letzteres bietet mehr diagnostische Schwierigkeiten.
Ebenso gibt es Mischformen mit Anteilen von beiden Typen.
Unter Halluzination versteht man eine Wahrnehmung eines Sinnesgebietes, ohne dass eine
nachweisbare Reizgrundlage vorliegt. Das bedeutet zum Beispiel, dass physikalisch nicht
nachweisbare Objekte gesehen werden oder Stimmen gehört, ohne dass jemand spricht.
Halluzinationen können alle Sinnesgebiete betreffen. Bei einer Illusion hingegen wird ein real
vorhandener Sachverhalt verändert wahrgenommen: Ein tatsächlich vorhandener feststehender
Gegenstand scheint sich zu bewegen oder in irregulären Mustern werden scheinbar Gesichter
erkennbar. Bei optischen Halluzinationen kommt es zur Wahrnehmung nicht vorhandener
Objekte. Am häufigsten sind kleine und bewegliche Objekte, deren Wahrnehmung dann meist
sehr angstvoll erlebt wird. Dies kommt beispielsweise im Rahmen eines Deliriums vor. Bei
akustischen Halluzinationen, die beispielsweise bei an Schizophrenie Erkrankten häufig sind,
hören die Betroffenen oft imperative Stimmen.

Cognitive Trajectories after Postoperative Delirium
Delirium is common after cardiac surgery and may be associated with long-term changes in
cognitive function. We examined postoperative delirium and the cognitive trajectory during the first
year after cardiac surgery. We enrolled 225 patients 60 years of age or older who were planning to
undergo coronary-artery bypass grafting or valve replacement. Patients were assessed
preoperatively, daily during hospitalization beginning on postoperative day 2, and at 1, 6, and 12
months after surgery. Cognitive function was assessed with the use of the Mini–Mental State
Examination (MMSE; score range, 0 to 30, with lower scores indicating poorer performance).
Delirium was diagnosed with the use of the Confusion Assessment Method. We examined
performance on the MMSE in the first year after surgery, controlling for demographic
characteristics, coexisting conditions, hospital, and surgery type.

Confusion Assessment Method (CAM; a
diagnostic algorithm to determine the presence
or absence of delirium on the basis of four
features: acute change with a fluctuating course,
inattention, disorganized thinking, and altered
level of consciousness), and the Delirium
Symptom Interview (an interview that assesses
the presence or absence of eight features of
delirium, including the four features of the CAM
diagnostic algorithm).
The 103 participants (46%) in whom delirium
developed postoperatively had lower
preoperative mean MMSE scores than those in
whom delirium did not develop (25.8 vs. 26.9,
P

A Pooled Analysis of Vitamin D Dose Requirements for Fracture Prevention
The results of meta-analyses examining the relationship between vitamin D supplementation
and fracture reduction have been inconsistent. We pooled participant-level data from 11
double-blind, randomized, controlled trials of oral vitamin D supplementation (daily, weekly, or
every 4 months), with or without calcium, as compared with placebo or calcium alone in
persons 65 years of age or older. Primary end points were the incidence of hip and any
nonvertebral fractures according to Cox regression analyses, with adjustment for age group,
sex, type of dwelling, and study. Our primary aim was to compare data from quartiles of actual
intake of vitamin D (including each individual participant's adherence to the treatment and
supplement use outside the study protocol) in the treatment groups of all trials with data from
the control groups.

In conclusion, our data suggest that high-dose vitamin D supplementation (≥800 IU per
day) may reduce the risk of hip fracture in persons 65 years of age or older, independently
of type of dwelling, age, and sex. Furthermore, our data support a 25-hydroxyvitamin D
level above 60 nmol per liter for the prevention of fractures.

Shock-Wave Lithotripsy for Renal Calculi
A 42-year-old man without a history of kidney stones had intermittent left flank pain for several
weeks before being seen by his primary care doctor. Urinalysis revealed microhematuria.
Computed tomography (CT) of the abdomen and pelvis without contrast enhancement identified
a calcification 12 mm in diameter in the left renal pelvis, associated with mild hydronephrosis and
a normal-caliber ureter. The attenuation coefficient of the stone was 790 Hounsfield units, and the
skin-to-stone distance was 8.5 cm. He was referred to a urologist, who reviewed the CT scan and
recommended treatment with extracorporeal shock-wave lithotripsy.
Nephrolithiasis is a common condition, with a lifetime prevalence of approximately 13% in men
and 7% in women in the United States. Total health care expenditures reached nearly $4.5 billion
annually, and this figure increased to $5.3 billion when the indirect costs of lost workdays were
included.

European Association of Urology Urolithiasis Guideline Panel released comprehensive
guidelines,45 recommending shock-wave lithotripsy as first-line therapy for non–lower-pole renal
calculi less than 2 cm in diameter and for lower-pole renal calculi less than 1 cm in diameter. For
larger stones in either location, percutaneous nephrolithotomy is the recommended primary
treatment. For lower-pole stones between 1 and 2 cm in diameter without unfavorable
anatomical factors or shock-wave–resistant stone composition, lithotripsy can be considered as
an option for primary management.
The patient described in the vignette has a stone with a size (less than 2 cm in diameter) and
location (non–lower pole) that is considered to be favorable for treatment with shock-wave
lithotripsy. Findings on CT imaging, including the attenuation coefficient (less than 1000
Hounsfield units) and the skin-to-stone distance (less than 10 cm), also predict a favorable
outcome. Although the stone composition cannot be reliably predicted by means of current CT
findings, and the patient did not previously have a stone with a known composition, the favorable
findings on CT suggest that the stone will probably fragment well and that the risk of obstructive
complications will be low.
Bei diesem Verfahren benötigt der Patient keine Vollnarkose, in
der Regel wird nur ein leichtes Schmerzmittel intravenös
verabreicht, der Patient bleibt ansprechbar. Gegen den bei der
Behandlung entstehenden Lärm (rund 3000 niedrigfrequente
Impulse in 30 Minuten) bekommt der Patient einen Gehörschutz.
Sehr oft kann diese Behandlung auch ambulant durchgeführt
werden. Die Belastung für den Patienten ist gering und durch die
gezielte Bündelung der Stoßwellen weniger schmerzhaft als bei
den Geräten erster Bauart mit Badewanne.

A 31-year-old woman who had been unable to eat or drink for the preceding week was admitted
to the hospital. For the preceding 8 months she had had nausea, vomiting, and abdominal
discomfort and several episodes of crampy epigastric pain with vomiting and intermittent chills
and sweats, but no documented fevers. She also had loose, pale stools occasionally, but these
episodes did not represent a notable change from her baseline. Gradually increasing fatigue,
loss of appetite, and a recent weight loss of several kilograms were also reported. The patient's
medical history included hypertension, obesity, and migraine headaches. She had undergone
Roux-en-Y gastric bypass 5 years before presentation and subsequently lost approximately 45
kg (100 lb). Her weight had been stable for the past few years; her body-mass index (BMI, the
weight in kilograms divided by the square of the height in meters) was 33. She had undergone
laparoscopic cholecystectomy 10 years before presentation. Her only medication was nifedipine,
and she took a multivitamin on occasion. Intravenous fluids were administered (1 liter of 0.90%
sodium chloride followed by a continuous infusion of 5% dextrose in a solution of 0.45% sodium.
chloride). The hematocrit was 29.4%, with a mean corpuscular volume
of 109 fl. The white-cell count was 9350 per cubic millimeter
and her platelet count 432,000 per cubic millimeter. The
aspartate aminotransferase level was 210 U per liter, alanine
aminotransferase 44 U per liter, alkaline phosphatase 191 U
per liter, total bilirubin 0.6 mg per deciliter (10.3 µmol per
liter), albumin 3.3 g per deciliter, prothrombin time 13.6
seconds, and partial-thromboplastin time 33.8 seconds.
Amylase and lipase levels were normal, and a serum test for
beta human chorionic gonadotropin was negative. Abdominal
computed tomography revealed a diffusely fatty liver, with
focal sparing of the medial portion of the right lobe, and
hepatomegaly, with a liver span of 26.5 cm; the spleen,
measuring 14.2 cm, showed borderline enlargement.

On the second hospital day, confusion, blurry vision, and vertigo developed abruptly. A repeat
examination revealed impaired lateral gaze in both eyes and nystagmus on both horizontal and
upward gaze, with a positive Romberg test. The patient was noted to have a wide-based,
unsteady gait and was able to take only a few steps, with assistance from two people.
Enlargement of the mammillary bodies is shown in an image
obtained with fluid-attenuated inversion recovery sequencing
(Panel A, arrow), and enhancement is shown in a T1weighted
magnetic resonance image obtained after the
administration of contrast material (Panel B). The patient was
given 500 mg of thiamine intravenously on an emergency
basis. Subsequent testing revealed low levels of whole-blood
thiamine (45 nmol per liter; normal range, 80 to 150) and of
serum folate (4.6 ng per milliliter [10.4 nmol per liter]; normal
range, 5.3 to 9.9 ng per milliliter [12.0 to 22.4 nmol per liter]),
copper (46 µg per deciliter [7.2 µmol per liter]; normal range,
80 to 155 µg per deciliter [12.6 to 24.4 µmol per liter]), zinc
(57 µg per deciliter [8.7 µmol per liter]; normal range, 66 to
120 µg per deciliter [10.0 to 18.4 µmol per liter]), and 25hydroxyvitamin
D (6 ng per milliliter [15 nmol per liter];
normal range, 25 to 80 ng per milliliter [62 to 200 nmol per
liter]).

Die Hand-Fuß-Mund-Krankheit – Synonyme: Hand-Fuß-Mund-Exanthem, Falsche Maul- und
Klauenseuche – ist eine viral bedingte, weltweit vorkommende, hoch ansteckende und deshalb
epidemisch auftretende Infektionskrankheit. Nach einer durchschnittlichen Inkubationszeit von
drei bis sechs Tagen kommt es in der Regel zu einer Erkrankung mit hohem Fieber,
vorübergehenden Allgemeinsymptomen und einem symmetrischen Hautausschlag (Exanthem)
mit Bläschenbildung an den Händen, Füßen und einem Enanthem der Mundschleimhaut, das
sich mit kurzlebigen Bläschen von vier bis acht Millimeter Durchmesser in der Mundhöhle, vor
allem im Bereich der Zunge, des Gaumens und der Wangenschleimhaut äußert. Lippen, weicher
Gaumen, Tonsillen und Pharynx bleiben frei bzw. sind selten betroffen. Diese Bläschen wandeln
sich in seichte, schmierig belegte, schmerzhafte Erosionen (Aphthen). Die Veränderungen an
Händen und Füßen treten gleichzeitig oder nur kurze Zeit später auf und sind vermehrt an den
Streckseiten der Finger und Zehen oder deren Seitenflächen, aber auch den Fußsohlen (Fersen)
und Handflächen zu beobachten. Hände und Füße können dabei einen stechenden /
spannenden Schmerz und starken Juckreiz aufweisen. Diese Erkrankung wird durch eine
Infektion mit Coxsackie- (Typ A 5, 9, 10, 16, B2, 5), Echo- (Typ 6) oder Enteroviren (Humanes
Enterovirus 71) verursacht. Möglicherweise verlaufen bis zu 70 % der Infektionen
asymptomatisch (inapparente Infektion).

Autopsy Findings in Children with Hand, Foot, and Mouth Disease
(etwa wie Maul und Klauenseuche)
From May 2008 through July 2010, an epidemic of hand, foot, and mouth disease occurred in
Guangxi, China. During the epidemic, some children died of progressive cardiorespiratory
failure. Postmortem pathological examinations were performed for 14 patients. Reversetranscriptase–polymerase-chain-reaction
assays of various specimens (throat swabs or stool
samples) were performed to detect enterovirus 71, coxsackievirus A17, and pan-enterovirus
messenger RNA. Assays for enterovirus 71 were positive in 12 patients. Assays to detect
coxsackievirus A17 were positive in 1 patient, and assays to detect other enteroviruses were
positive in 1 patient.
Sections of brain-biopsy specimens were
stained with hematoxylin and eosin. A
photomicrograph at low magnification
(Panel A) shows neuronal necrosis and
softening in the brain stem (arrow), and
higher magnification (Panel B) reveals the
neuronophagia phenomenon (blue arrow)
and colloid (black arrow) in the brain stem.
A photomicrograph at low magnification
(Panel C) shows perivascular cuffing in the
brain stem (arrow). A view of the medulla
oblongata at low magnification (Panel D)
shows hemorrhage (arrow).

A 68-year-old man complained of urinary frequency and hypogastric discomfort. He was a
smoker and had hypertension. Digital rectal examination showed a painful prostate but he had no
fever. Urine analysis showed a pyuria and a bacteriuria of enterococcus species. The patient was
treated with amoxicillin. 2 days after his admission, he suddenly developed acute right flank pain
with hypotension.
(A) Axial non-contrast-enhanced MDCT of the abdomen showing retroperitoneal haematoma (asterisk)
surrounding a fissured infrarenal abdominal aneurysm (arrowheads). Contrast-enhanced MDCT angiography in
axial (B) and sagittal (C) reformation with maximum intensity projection algorithm; CT angiogram shows
anterior rupture from the wall of the abdominal aortic aneurysm (arrow), with massive intraperitoneal bleeding
(contrast extravasation).

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme which in
humans is encoded by the PCSK9 gene. The encoded protein is synthesized as a soluble
zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum.
The protein may function as a proprotein convertase. This protein plays a major regulatory role in
cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A)
domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced
LDLR levels result in decreased metabolism of low-density lipoproteins, which could lead to
hypercholesterolemia. Alnylam Pharmaceuticals has recently shown, in initial clinical trials,
positive results of ALN-PCS, which acts by means of RNA interference, as an effective means of
PCSK9 inhibition. Mutations in this gene have been associated with a rare form of autosomal
dominant familial hypercholesterolemia (HCHOLA3). The mutations appear to cause the disease
by increasing its protease activity, reducing LDL receptor levels and thereby preventing the
uptake of cholesterol into the cells.

Effect of a monoclonal antibody to PCSK9, to reduce low-density lipoprotein
cholesterol in patients with heterozygous familial hypercholesterolaemia on
stable statin dose with or without ezetimibe therapy: a phase 2 trial
Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in
large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed
the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal
antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous
familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial
was done at 16 lipid clinics, we enrolled adults with heterozygous familial
hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and
statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727
150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2
weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at
baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was
maintained by administration of placebo alternating with REGN727 for the groups of 4 week
dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12
and was analysed in the modified intention-to-treat population with an analysis of covariance
(ANCOVA) model with treatment group.

REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with
heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose
statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of
LDL-C in patients with this disorder.

Epidemiology of multimorbidity and implications for health care, research, and
medical education: a cross-sectional study
Long-term disorders are the main challenge facing health-care systems worldwide, but health
systems are largely configured for individual diseases rather than multimorbidity. We examined
the distribution of multimorbidity, and of comorbidity of physical and mental health disorders, in
relation to age and socioeconomic deprivation. In a cross-sectional study we extracted data on
40 morbidities from a database of 1 751 841 people registered with 314 medical practices in
Scotland as of March, 2007. We analysed the data according to the number of morbidities,
disorder type (physical or mental), sex, age, and socioeconomic status. We defined
multimorbidity as the presence of two or more disorders.

Our findings challenge the single-disease
framework by which most health care, medical
research, and medical education is configured.
A complementary strategy is needed, supporting
generalist clinicians to provide personalised,
comprehensive continuity of care, especially in
socioeconomically deprived areas.

Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a
randomised placebo-controlled trial
Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal
subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed
cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after
aneurysmal subarachnoid haemorrhage. We did this phase 3 randomised, placebo-controlled
trial in eight centres in Europe and South America. We randomly assigned (with computergenerated
random numbers, with permuted blocks of four, stratified by centre) patients aged
18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging
who were admitted to hospital within 4 days of haemorrhage, to receive intravenous
magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or
bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing
outcomes and analysing data were masked to the allocation. The primary outcome was poor
outcome—defined as a score of 4—5 on the modified Rankin Scale—3 months after
subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also
updated a previous meta-analysis of trials of magnesium treatment for aneurysmal
subarachnoid haemorrhage.

The MASH 2 trial has implications for clinical
practice. Administration of magnesium after
aneurysmal subarachnoid haemorrhage is
standard practice in many centres. On the basis
of the results of MASH 2—a trial of treatment of
aneurysmal subarachnoid haemorrhage with
sufficient power to detect a clinically significant
improvement in outcome—and in combination
with data from other trials, we do not
recommend routine use of intravenous
magnesium 64 mmol/day for the improvement of
outcome after aneurysmal subarachnoid
haemorrhage.

The 10/66 Dementia Research Group is a collective of researchers carrying out populationbased
research into dementia, non-communicable diseases and ageing in low and middle
income countries.10/66 refers to the two-thirds (66%) of people with dementia living in low and
middle income countries, and the 10% or less of population-based research that has been
carried out in those regions.10/66 is a part of Alzheimer's Disease International, and is coordinated
from the Institute of Psychiatry, King's College London.
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). DSM-IV
manual is published by the American Psychiatric Association and covers all mental health
disorders for both children and adults. It also lists known causes of these disorders, statistics in
terms of gender, age at onset, and prognosis as well as some research concerning the optimal
treatment approaches. Mental Health Professionals use this manual when working with patients
in order to better understand their illness and potential treatment and to help 3rd party payers
(e.g., insurance) understand the needs of the patient. The book is typically considered the
‘bible’ for any professional who makes psychiatric diagnoses in the United States and many
other countries. Much of the diagnostic information on these pages is gathered from the DSM
IV.

Dementia incidence and mortality in middle-income countries, and
associations with indicators of cognitive reserve
Results of the few cohort studies from countries with low incomes or middle incomes suggest a
lower incidence of dementia than in high-income countries. We assessed incidence of dementia
according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical
Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the
independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. We
did a population-based cohort study of all people aged 65 years and older living in urban sites in
Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and
China, with ascertainment of incident 10/66 and DSM-IV dementia 3—5 years after cohort
inception. We used questionnaires to obtain information about age in years, sex, educational
level, literacy, occupational attainment, and number of household assets. We obtained
information about mortality from all sites. For participants who had died, we interviewed a friend
or relative to ascertain the likelihood that they had dementia before death.

In this study of more than 12 800 individuals, incidence rates for 10/66 dementia were roughly 1·5
—2·5 times higher than those for DSM-IV dementia. Mortality hazards were higher in individuals
with dementia at baseline than in dementia-free individuals. Informant reports suggested a high
incidence of dementia before death; overall incidence could be between 4% and 19% higher if
these data were included. 10/66 dementia incidence was independently associated with increased
age, female gender, and low education, but not with occupational attainment. Our results provide
supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries
as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer
substantial protection against the onset of dementia.

Sport and exercise as contributors to the health of nations
Self-reported rates of participation in sport vary by country. In the UK, about 40% of men and
women aged 16 years or older participate in at least one sport every week. Although few data exist
to assess trends for participation in sport, there is little evidence of change in the past decade
among adults. Large cohort studies suggest that such participation in sport is associated with a 20
—40% reduction in all-cause mortality compared with non-participation. Randomised trials and
crossover clinical studies suggest that playing sport is associated with specific health benefits.
Some sports have relatively high injury risk although neuromuscular training programmes can
prevent various lower extremity injuries. Clinicians can influence a large number of patients through
brief interventions that promote physical activity, and encouragement toward participation in sport
for some physically inactive patients qualifies as evidence-based therapy. Exercise might also be
considered as a fifth vital sign and should be recorded in patients' electronic medical records and
routine histories.
Sport, exercise, and physical activity
(A) Domains of sport, exercise, and physical activity. (B)
Individual who exercises and plays sport but is otherwise
sedentary. (C) Physically active individual who does no explicit
sport or exercise.

39-year-old woman presented complaining of a 1-day history of vomiting and abdominal pain.
She had had three or four episodes, with no infective prodrome. She was a physiotherapist and
a competent long-distance runner; 2 days earlier she had run a 5 km race, and that morning
had done her daily exercise workout. On examination there were no physical signs other than
sinus tachycardia. Within 2 h, she collapsed and was moribund in acute cardiogenic shock.
Chest radiography showed pulmonary congestion. Transthoracic echocardiography showed a
slightly dilated, poorly functioning heart with no pericardial effusion. Cardiac catheterisation was
done to exclude coronary artery disease, and an intra-aortic balloon pump was placed for
circulatory support. She had no arrhythmias. Acute myocarditis was suspected and she was
transferred to our cardiothoracic centre. She arrived 8 h after first presentation, was found to be
in extremis, with fixed mottling of her trunk and limbs and hypotension despite epinephrine
infusing at >1 µg/kg per min. She was anuric, profoundly acidaemic, and hypoxic on 100%
oxygen (PaO2 6·1 kPa, pH 6·9, lactate 16 mmol/L, base excess −13). The heart was tense and
dilated and a myocardial biopsy sample was taken from the left ventricle. Central veno-arterial
extracorporeal membrane oxygenation (ECMO) was established; a cannula was inserted via
the abdominal wall into the right atrium to drain systemic venous blood into the ECMO pump,
which returned oxygenated blood via a separate cannula into the ascending aorta
CT of the abdomen showed a large left adrenal mass (5×6 cm).
Left adrenalectomy was done (day 3) with concurrent ECMO
support. Subsequent echocardiography showed recovering
biventricular function (day 5) and ECMO was discontinued.

Myocyte necrosis with contraction bands,
perivascular edema, and microvascular
endothelial swelling with no evidence of
myocarditis. Immunohistochemical staining for
C4d was strongly positive along the
microvasculature and in rare individual myocytes
with contraction band injury
Hematoxylin & eosin, 10X. Myocardium with
coagulative myocyte necrosis in center and lower right
corner.