Convergent strabismus
Immature cataract
Intraocular tumor
Retinitis pigmentosa
Tay-Sachs disease
Unequal intensity of the red reflexes suggests unequal refractive power, ocular media
opacities, or fundus disease. Any divergence in red-reflex intensity warrants referral to an
ophthalmologist. This child did well following enucleation for a retinoblastoma.
Die Bezeichnung Retinopathia
pigmentosa oder Retinitis pigmentosa
(RP) beschreibt eine durch Vererbung
oder spontane Mutation entstehende
Netzhautdegeneration, bei der die
Photorezeptoren zerstört werden.
Tay–Sachs disease (also known as GM2 gangliosidosis
or hexosaminidase A deficiency) is an autosomal
recessive genetic disorder.
Das Retinoblastom-Protein (pRb, Rb) ist ein Tumorsuppressor-Protein, das bei vielen Tumoren
eine gestörte Funktion besitzt. Eine sehr gut untersuchte Funktion von pRB ist es, das
Zellwachstum zu verlangsamen, indem der Durchlauf des Zellzyklus gebremst wird. pRB gehört
zu der sogenannten Pocket-Protein-Familie. Deren Mitglieder besitzen für die Bindung an
andere Proteine eine molekulare Tasche. Wenn Onkogen-Produkte, wie sie etwa in Zellen
produziert werden, die von menschlichen Papillomaviren infiziert wurden, an pRB binden, dann
kann dies zu Krebs führen. Es ist bislang ungeklärt, wieso sich bei Mutationen eines Gens, das
den Zellzyklus im ganzen menschlichen Organismus reguliert, ein Tumor der Augen entwickelt.
How the tumor-suppressor genes Rb and p16 interact to block cell division. The retinoblastoma
protein (Rb) binds to the transcription factor (E2F) that activates genes in the nucleus, preventing this
factor from initiating mitosis. The G1 checkpoint is passed when Cdk interacts with cyclins to
phosphorylate Rb, releasing E2F. The p16 tumor-suppressor protein reinforces Rb’s inhibitory action
by binding to Cdk so that Cdk is not available to phosphorylate Rb.
The RAS/RAF/MAP kinase-ERK kinase (MEK)/extracellularsignal-regulated kinase (ERK) (MAPK) and the PI3K/AKT/
mammalian target of rapamycin (mTOR) (PI3K) pathways are
frequently deregulated in human cancer as a result of genetic
alterations in their components or upstream activation of cellsurface receptors.
Wo funktioniert MEK im MAPKinase Ablauf? Unter anderem an
der Regulation der Embryogenese, der Zelldifferenzierung, des
Zellwachstums und des Programmierten Zelltodes beteiligt
sind. Die Signalwege umfassen mindestens drei „in Serie“
geschaltete Kinasen (siehe Abbildung): Eine MAP-KinaseKinase-Kinase (MAP-3K, auch MAP-KKK), eine MAP-KinaseKinase (MAP-2K, auch MAP-KK) und eine MAP-Kinase (MAPK), welche in dieser Reihenfolge aktiviert (phosphoryliert)
werden. Man spricht hier auch von
Phosphorylierungskaskaden. Aktivierung über Mitogene
(aktiviert die Kaskade Raf → MEK 1/2 → ERK 1/2 und wird
auch ERK1/ERK2 Kaskade genannt), was zu Zellwachstum,
Zellproliferation und Differenzierung führen kann. Dieser
Signalweg ist bei 30 % aller Krebsarten hyperaktiviert.
Also MEK ist die MAP kinase-ERK kinase (MEK) in diesem
Ablauf
Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma
Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients
with advanced melanoma. Selective BRAF-inhibitor (sorafenib) therapy improves survival, as
compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition
appeared to be promising in this population. In this phase 3 open-label trial, we randomly assigned
322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive
either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received
trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of bodysurface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy
group who had disease progression were permitted to cross over to receive trametinib.
Progression-free survival was the primary end point, and overall survival was a secondary end
point.
The most common adverse events
in the trametinib group were rash,
diarrhea, peripheral edema,
fatigue, and dermatitis acneiform;
among the patients with rash, less
than 8% had grade 3 or 4 rash. A
decreased ejection fraction or
ventricular dysfunction was
observed in 14 patients (7%) in the
trametinib group (11 with a
decreased ejection fraction and 3
with left ventricular dysfunction).
ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the
KCNJ10 gene. This gene encodes a member of the inward rectifier-type potassium channel family,
Kir4.1, characterized by having a greater tendency to allow potassium to flow into, rather than out
of, a cell. Kir4.1, may form a heterodimer with another potassium channel protein and may be
responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have
been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes.
Humans with mutations in the KCNJ10 gene that cause loss of function in related K+ channels can
display seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance
(SeSAME syndrome), reflecting roles for KCNJ10 gene products in the brain, inner ear and kidney.
The Kir4.1 channel is expressed in the Stria vascularis and is essential for formation of the
endolymph, the fluid that surrounds the mechanosensitive stereocilia of the sensory hair cells that
make hearing possible. KCNJ10 has been shown to interact with Interleukin 16.
Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system.
Many findings suggest that the disease has an autoimmune pathogenesis; the target of the
immune response is not yet known. We screened serum IgG from persons with multiple sclerosis
to identify antibodies that are capable of binding to brain tissue and observed specific binding of
IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane
proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target
of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of
the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo.
IgG heavy chain band
Panel A, left, shows a one-dimensional SDS-PAGE of human brain lysate precipitated with IgG
from the pooled serum of 12 patients with MS and 12 with other neurologic diseases (OND). (For
the middle lane [marked –], no brain lysate was used in the precipitation.) Unique bands (third
lane) above and below the IgG heavy chain band (arrow) are observed after immunoprecipitation
with purified IgG from the pooled serum of patients with MS. Panel A, right, shows a twodimensional electrophoresis of brain antigens obtained after immunoprecipitation with serum IgG
from patients with MS. The spot containing the KIR4.1 protein, identified by means of matrixassisted laser desorption–tandem mass spectrometry, is outlined with a square. The arrow
shows the IgG heavy chain spot.
Initially, the authors observed that serum IgG from patients with multiple sclerosis, but not that
from controls, bound a protein expressed in human and rodent brain.
They subsequently determined that the precise target of antibody binding was one of two
extracellular loops of KIR4.1.
They then devised an enzyme-linked immunosorbent assay to rapidly screen for antibodies to
KIR4.1. Remarkably, 186 of 397 serum samples from patients with multiple sclerosis, but only 3
of 329 samples from controls with other neurologic diseases and 0 of 59 samples from healthy
controls, had antibodies that bound KIR4.1. The anti-KIR4.1 IgG isotypes were primarily IgG1
and IgG3, which are capable of binding complement and thus mediating cell lysis.
When the authors injected human complement and anti-KIR4.1 IgG isolated from patients with
multiple sclerosis into the cisternae magnae of mice, they observed pathologic changes 24
hours later.
Although these neuropathologic changes did not resemble those of multiple sclerosis, 24 hours
is probably too short a time for pathologic features relevant to multiple sclerosis to develop fully.
Foremost is the question of whether these antibodies play a pathogenic role in multiple
sclerosis. It seems to be unlikely that antibodies to KIR4.1 are causative, since they were
identified in about half of persons with multiple sclerosis.
Panel B shows KIR4.1 detection by Western blot
analysis in two different immunoprecipitation (IP)
assays, as indicated. IP assays were performed
with serum IgG from patients with OND and from
patients with MS on membrane-protein–enriched
fractions of rat kidney and human brain tissue
lysates. The lanes on the left (marked –) of the
blots are negative controls (no IgG used for IP).
Panel C shows a Western blot analysis of
KIR4.1 immunoprecipitation from in vitro–
translated human KIR4.1 protein with serum IgG
from patients with OND and from patients with
MS.
Panel A shows double
immunofluorescence labeling revealing
colocalization of monoclonal anti-KIR4.1
with serum IgG from a patient with MS in
cerebellar sections of rat brain. Staining
with serum of a patient with other
neurologic diseases (OND) is shown as a
control (scale bar, 200 µm for all parts of
Panel A). Panel B shows
immunofluorescence labeling of cerebellar
sections of wild-type (left) and Kir4.1 –/–
(right) mice with purified serum IgG from a
patient with MS
A protein-based enzyme-linked immunosorbent assay (ELISA) was used to detect antiKIR4.1 serum autoantibodies. Purified recombinant KIR4.1 from HEK293 cells was
covalently coupled to ELISA plates. Serum antibody binding to KIR4.1 was determined in
healthy donors (HD), in patients with other neurologic diseases (OND), and in patients with
MS or a clinically isolated syndrome (CIS) for the discovery series (Panel A), the first
validation series (Panel B), and the second validation series (Panel C). For the first two
series, KIR4.1 antibody titers of healthy persons, of patients with OND, and of patients with
MS or a CIS were compared with the use of the Kruskal–Wallis test of one-way analysis of
variance followed by Dunn's multiple comparison test, for which P values are shown.
It is also possible that anti-KIR4.1 antibodies
may interfere with the channel function of
KIR4.1, resulting in a disruption of potassium
buffering and neurotransmitter homeostasis, and
thus tissue injury or impaired remyelination.
Phosphate-buffered saline, serum IgG
from a patient with MS depleted of
KIR4.1-specific antibodies
(preabsorbed, second row), or serum
IgG with preserved anti-KIR4.1
reactivity (third and fourth rows) was
injected into the cisternae magnae of
C57BL/6 mice together with human
complement. 24 h after injection, the
mice were killed and brain sections
were assessed for glial fibrillary acidic
protein (Gfap) expression (left column),
Kir4.1 expression (middle column), and
C9neo reactivity (right column). the
mice injected with KIR4.1-reactive
serum IgG showed alteration of Gfap
expression, loss of Kir4.1 expression,
and C9neo deposits. The loss of
parenchymal Kir4.1 was most
pronounced in the vicinity of the
subarachnoid space and less
pronounced with increasing distance
from the subarachnoid space. C9neo
deposits were locally restricted to
regions of Kir4.1 depletion.
Hydroxyethylstärke, abgekürzt HES oder HAES (früher auch: HÄS), ist ein künstlich hergestelltes
Polymer. Es wird unter anderem als Blutplasmaersatzstoff verwendet. HES dient dabei als
kolloidaler Volumenersatz, der wie die Dextrane und Gelatine zum Ausgleich eines intravaskulären
Volumenmangels eingesetzt wird. Hergestellt wird HES aus Wachsmaisstärke oder aus
Kartoffelstärke. Damit besteht er fast ausschließlich aus Amylopektin, also aus verzweigten Ketten
von Glucosemolekülen. Um einen zu schnellen Abbau des Amylopektins durch das endogene
Enzym Amylase zu verhindern, erfolgt eine teilweise Hydroxyethylierung der Glucoseeinheiten.
Diese Hydroxyethylierung ist auch notwendig um eine Wasserlöslichkeit von Stärke zu erreichen.
Waren in der ersten Generation die durchschnittliche Molekülgröße meist 450.000 Dalton und der
Substitutionsgrad betrug 0,7, so reduzierten sich diese in der zweiten Generation auf 200.000 und
0,5 und in der dritten Generation auf 130.000 und 0,4. In den USA ist weiterhin nur die erste
Generation als Hetastarch verfügbar, während die zweite Generation als Pentastarch nur
bestimmten Anwendungen vorbehalten bleibt. Heutige moderne HES haben neben einer weiter
reduzierten molaren Masse von ca. 130.000 mit einem Substitutionsgrad von 0,4 auch nicht mehr
Kochsalzlösung zur Aufrechterhaltung der Isotonie, sondern eine balancierte Lösung mit Azetat.
Joachim Boldt (* 29. September 1954) ist ein deutscher Anästhesiologe. Er galt als einer der
führenden Forscher auf dem Gebiet kolloidaler Infusionslösungen, bis er des
Wissenschaftsbetrugs durch Datenfälschung und Missachtung ethischer Standards verdächtigt
wurde. Boldt verlor am 26. November 2010 seine Stelle als Chefarzt für Anästhesiologie und
Intensivmedizin am Klinikum Ludwigshafen. Er trat aus der Deutschen Gesellschaft für
Anästhesiologie und Intensivmedizin aus. Seine außerplanmäßige Professur wurde ihm von der
Justus-Liebig-Universität Gießen aberkannt. Bereits 2005 hatte die Gießener Staatsanwaltschaft
gegen Boldt und Kollegen wegen Datenmanipulation und illegaler Studien am Menschen mit
Hydroxyethylstärke (HES) ermittelt. Der Fall machte nach einer Veröffentlichung in der Gießener
Allgemeinen Zeitung bundesweit Schlagzeilen. Die Vorwürfe konnten jedoch nicht belegt werden.
Rund 70 Fachartikel hatte Boldt über Hydroxyethylstärke veröffentlicht, meist mit positiver
Bewertung des Medikaments. Am 28. Oktober 2010 hat der Herausgeber der Zeitschrift
Anesthesia & Analgesia eine Publikation Joachim Boldts zurückgezogen, die 2009 publiziert
worden war. Nach Zweifeln an der Korrektheit der Daten war eine wissenschaftliche Kommission
zu dem Schluss gekommen, dass es keinen überzeugenden Beweis dafür gibt, dass die der
Veröffentlichung zugrundeliegende Studie durchgeführt wurde
Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis
Hydroxyethyl starch (HES) 130/0.42 is widely used for fluid resuscitation in intensive care units
(ICUs), but its safety and efficacy have not been established in patients with severe sepsis. In
this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis
to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a
dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure
was either death or end-stage kidney failure (dependence on dialysis) at 90 days after
randomization.
In conclusion, patients with severe sepsis who received fluid resuscitation with HES 130/0.42, as
compared with those who received Ringer's acetate, had a higher risk of death at 90 days, were
more likely to receive renal-replacement therapy, and had fewer days alive without renalreplacement therapy and fewer days alive out of the hospital.
Unter der Graft-versus-Host-Reaktion (GvHR; deutsch: Transplantat-Wirt-Reaktion; englisch:
Graft-versus-Host-Disease (GvHD)) versteht man eine immunologische Reaktion, welche in der
Folge einer allogenen Knochenmark- oder Stammzelltransplantation auftreten kann. Bei der
GvHR reagieren vor allem die im Transplantat enthaltenen T-Lymphozyten eines Spenders
gegen den Empfängerorganismus. Am häufigsten äußern sich Symptome der GvHR an der
Haut, der Leber, am Darm und am Auge. Die GvHR wird dabei nach Ausprägung und Anzahl
der befallenen Organe in vier Schweregrade eingeteilt. Das Risiko, eine GvHR zu entwickeln,
hängt eng mit der Kompatibilität zusammen, welche durch das humane Leukozyten-Antigen
(HLA) bestimmt wird. Bei allogener Transplantation von HLA-identischen Geschwisterspendern
entwickeln jedoch trotz optimaler Vorsorge ca. 30 bis 40 % der Patienten eine akute GvHR
leichter bis mittlerer Ausprägung; ca. 10 % erleiden eine schwer kontrollierbare GvHR[3].
Verschiedene Techniken der Aufbereitung von Transplantaten haben zwar das Risiko von
GvHR und therapieassoziiertem Frühversterben (early treatment related mortality, TRM)
verkleinert, sie führte jedoch nicht zu einer messbaren Erhöhung der Überlebensrate [4].
Immunsuppressiva wie Ciclosporin, Kortikosteroide, Antimetabolite und monoklonale
Antilymphozyten-Antikörper werden heute routinemäßig eingesetzt, um die GvHR besser
kontrollieren zu können. Obwohl die GvHR bei allogenen Stammzell- oder Knochenmarktransplantationen ein beträchtliches Gesundheitsrisiko darstellt, kann eine moderate Form der
GvHR dem Empfänger auch nutzen, da T-Zellen des Transplantats auch etwaige verbliebene
Tumorzellen des Wirtes zerstören (Graft-versus-Malignancy-Effekt).
CCR5 (CC-Motiv-Chemokin-Rezeptor 5, auch CD195, CMKBR5 oder CC-CKR5) ist die
Bezeichnung für ein Rezeptorprotein aus der Familie der Chemokinrezeptoren und für eben
dieses Rezeptorprotein exprimierende Gen. Der Rezeptor CCR5 ist ein essentieller Co-Rezeptor
bei der sexuellen Übertragung von HIV und ein wichtiger Co-Rezeptor allgemein im weiteren
Infektionsverlauf. Er ermöglicht das Andocken von HI-Viren an Makrophagen und manchen TLymphozyten, deren Aufnahme in die Zelle und somit dessen Infektion. Daher ist die Entwicklung
von Arzneistoffen, welche die Anbindung von HIV an CCR5 hemmen, von großem Interesse und
führte beispielsweise zum ersten zugelassenen Entry-Inhibitor Maraviroc. Darüber hinaus wird
CCR5 eine Beteiligung an Autoimmunerkrankungen wie multipler Sklerose, rheumatoider Arthritis
und Diabetes mellitus vom Typ I zugeschrieben. Eine Mutation des CCR5 Gens mit der
Bezeichnung CCR5Δ32 (CCR5-Delta32), bei der ein 32-Basenpaar-Segment deletiert ist, führt zu
einem Frameshift mit einem vorzeitigen Stoppcodon. Das daraus resultierende verkürzte Protein
(es fehlen die drei C-terminalen Transmembrandomänen) bleibt im Zytoplasma und wird nicht zur
Zelloberfläche transportiert. Dies hat eine Resistenz der Träger gegenüber den meisten HIVStämmen zur Folge.
By binding to CCR5 (left) and promoting its
sequestration (right), CCL3L1 can block HIV
replication. As a CCR5 agonist (center), CCL3L1
also can promote T cell activation and migration,
enhancing both cellular immunity and
generalized immune activation. Genetic
polymorphisms thought to determine the amount
of CCR5 and CCL3L1 have complex effects on
HIV pathogenesis that include control of viremia
and cellular immunity, as well as effects that are
independent of both.
Blockade of Lymphocyte Chemotaxis in Visceral Graft-versus-Host Disease
Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stemcell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity.
We tested whether CCR5 blockade would be safe and limit GVHD in humans. We tested the in
vitro effect of the CCR5 antagonist maraviroc on lymphocyte function and chemotaxis. We then
enrolled 38 high-risk patients in a single-group phase 1 and 2 study of reduced-intensity allogeneic
HSCT that combined maraviroc with standard GVHD prophylaxis.
Recruitment of lymphocytes
into tissues plays a major role
in GVHD. CCR5 is critical for
lymphocyte recruitment to
tissues involved in GVHD.
Maraviroc (Selzentry, Pfizer
and ViiV Healthcare) is the
first drug in the class of CCR5
antagonists.
Specific Inhibition of CCL5and CCL3-Induced
Internalization of CCR5 and
Inhibition of T-Cell
Chemotaxis Associated with
Maraviroc.
In Panel A, a representative
flow-cytometric analysis
shows a reduction in surface
expression of CCR5 on
normal donor CD8+ T cells
after incubation with 100 nM
of CCL5 for 30 minutes.
Preincubation with 1 µM of
maraviroc (MVC) for 30
minutes fully abrogated
internalization of the receptor.
Clinical Trial Outcomes of Acute
GVHD, Moderate-to-Severe
Chronic GVHD, and OrganSpecific Acute GVHD.
Inhibition of CCL5-Induced
CCR5 Internalization and CCL5Induced T-Cell Chemotaxis by
Serum from Patients Receiving
Maraviroc.
In this study, inhibition of
lymphocyte trafficking was a
specific and potentially effective
new strategy to prevent visceral
acute GVHD.
Management of Opioid Analgesic Overdose
Opioid analgesic overdose is a preventable and potentially lethal condition that results from
prescribing practices, inadequate understanding on the patient's part of the risks of medication
misuse, errors in drug administration, and pharmaceutical abuse. Three features are key to an
understanding of opioid analgesic toxicity. First, opioid analgesic overdose can have lifethreatening toxic effects in multiple organ systems. Second, normal pharmacokinetic properties
are often disrupted during an overdose and can prolong intoxication dramatically. Third, the
duration of action varies among opioid formulations, and failure to recognize such variations can
lead to inappropriate treatment decisions, sometimes with lethal results.
Between 1997 and 2007, prescriptions for opioid analgesics in the United States increased by
700%; the number of grams of methadone prescribed over the same period increased by more
than 1200%. In 2010, the National Poison Data System, which receives case descriptions from
offices, hospitals, and emergency departments, reported more than 107,000 exposures to opioid
analgesics, which led to more than 27,500 admissions to health care facilities.
Onset and Duration of Action in
Therapeutic Dosing and Overdose of
Selected Opioid Analgesic Agents. The
difference between the clinical effects of
therapeutic use and poisoning for these
selected agents arises from the
toxicokinetics of overdose, patterns of
abuse, and the variation in drug effects in
special populations.
The sine qua non of opioid intoxication is
respiratory depression, but miosis and stupor
are often observed in poisoned patients.
Hypoxemia or ingestion of drugs that are
coformulated with acetaminophen can cause
hepatic injury; acute renal failure can result from
hypoxemia or precipitation of myoglobin due to
rhabdomyolysis. Opioid analgesics decrease
intestinal peristalsis by binding to opioid
receptors in the gut. Patients with stupor who
are motionless often have compressed fasciabounded muscle groups, culminating in the
compartment syndrome; they may also have
hypothermia as a result of environmental
exposure or misguided attempts at reversing
intoxication. Since fentanyl can be a source of
overdose, patients should be examined for the
presence of fentanyl patches.
Empirical trials are needed to determine the effective dose
of naloxone. Patients who do not have a response to an
initial dose of naloxone should receive escalating doses until
respiratory effort is restored. Naloxone, which is frequently
dispensed as an injectable solution in doses of 0.4 mg per
milliliter and 1 mg per milliliter for adults, is almost devoid of
adverse effects. Pediatric patients are defined as children
up to the age of about 5 years or with a body weight of up to
20 kg. Pediatric patients with opioid intoxication frequently
require larger doses of naloxone to reverse the effects of
overdose because of the relatively higher ingested dose per
kilogram of body weight.
Opioid analgesic overdose is a life-threatening condition, and the antidote naloxone may have
limited effectiveness in patients with poisoning from long-acting agents. The unpredictable clinical
course of intoxication demands empirical management of this potentially lethal condition.
A 27-Year-Old Man with Fatigue, Weakness, Weight Loss, and Decreased
Libido
Thirteen months before presentation, the patient reported weighing 108.9 kg, and began aerobic
exercises, 2 hours daily, and a calorie-restricted diet (2400 kcal daily), resulting in a loss of 36.3
kg in 10 months. Two months before evaluation, arm weakness, numbness and aching in his
legs, decreased libido with loss of morning erections, and a faint lacy rash on his legs
developed. He reportedly stopped aerobics, began lifting weights, and increased his caloric
intake, without improvement in his symptoms. On evaluation by his physician at another
hospital, the white-cell and differential counts and blood levels of calcium, lipids, prolactin,
thyrotropin, and vitamin D were normal; testing for IgA autoantibodies to transglutaminase and
screening tests for antinuclear antibodies, the human immunodeficiency virus (HIV), viral
hepatitis, and Lyme disease were negative; and testing for parvovirus suggested past infection.
On examination, the patient was cachectic
with bitemporal wasting. The abdomen was
flat and nontender, with striae without
pigmentation; the feet were slightly
edematous, with a blanching erythematous
macular rash on the dorsal surface. Proximal
muscles were weak, with severe wasting in
the thighs. The pubic-hair distribution was
classified as Tanner stage 5; phallus length
was 4 cm, and testicular volume was 15 ml
(estimated) bilaterally. Urinalysis and blood
levels of globulin, phosphorus, vitamin B12,
thyroxine, and leptin were normal; other test
results are shown.
On follow-up 6 days later, the weight had decreased to 50.2 kg
(BMI, 16.3); the patient was admitted to this hospital. Examination
revealed painful pitting (1+) edema to the mid-shins; tenderness of
the Achilles' tendons; xerosis of the legs with nearly platelike
scaling, blanchable eczematous erythema on the feet and legs,
sparse petechiae and reticulate violaceous discoloration, vertical
striae on the abdomen, mild hyperkeratosis with fissuring of both
soles, and diminished hair growth on the lower legs. Strength was
diminished in the legs more than in the arms; the proximal and
distal muscles were affected. Sensation and reflexes were normal.
Blood levels of carcinoembryonic antigen and tissue
transglutaminase IgA antibodies were normal, as were protein
electrophoresis and immunofixation
Coronal (Panel A) and sagittal (Panel B)
reformatted CT images of the thorax, obtained in
lung windows, show extensive
pneumomediastinum (arrows) surrounding the
esophagus and trachea and extending to the
fascial planes of the neck. Coronal (Panel C)
and axial (Panel D) T2-weighted half-Fourier
single-shot turbo spin–echo and forced recovery
images of the upper abdomen show abnormally
low T2-weighted signal in the liver and spleen
(white arrows), without a clinically significant loss
of signal in the pancreas (black arrows).
Cachexia is unintended weight loss due
to underlying chronic illness and is
typically associated with an inflammatory
state or a disorder of metabolism. This
patient does not have objective evidence
for either of these conditions. On at least
two occasions, the patient's C-reactive
protein level, a marker of inflammation,
was normal. His insulin level was low on
one measurement, a feature consistent
with starvation, not cachexia.
This patient's clinical presentation met
the definition of eating disorder not
otherwise specified (EDNOS), according
to the criteria of the Diagnostic and
Statistical Manual of Mental Disorders,
fourth edition, text revision (DSM-IV-TR)
EDNOS is a heterogeneous residual
category comprising, among other
presentations, subthreshold anorexia
nervosa, and it is the most prevalent
clinical diagnosis made for an eating
disorder.
A liver-biopsy specimen (Panel A, hematoxylin
and eosin) shows increased pigment in
centrilobular hepatocytes, a feature consistent
with lipofuscin. In Panel B, Prussian blue
staining shows mildly increased hemosiderin in
some hepatocytes (arrows) and in Kupffer cells
(arrowheads). An Epon-embedded section from
a peripheral-nerve–biopsy specimen (Panel C,
toluidine blue) shows a degenerating axon
(asterisk). Frozen sections of muscle-biopsy
specimens from the patient (Panel D, periodic
acid–Schiff) and from a control patient (inset)
show marked depletion of glycogen in all this
patient's muscle fibers. A skin-biopsy specimen
(Panel E, hematoxylin and eosin) shows serous
atrophy of subcutaneous fat.
Once we started feeding him, the levels of liver aminotransferases rapidly improved. He
remained in the hospital for 25 days and insisted on being discharged. At the time of
discharge, his weight was 51 kg. He refused to pursue additional inpatient psychiatric
treatment for his eating disorder. He was referred to outpatient treatment with a
multidisciplinary team from the psychiatry and nutrition departments, as well as his primary
care physician.
A 51-year-old woman with type 2 diabetes, and hypertension presented with
central weight gain and proximal muscle weakness.
CT showed an enlarged left adrenal gland with two distinct tumours.
Hypervascularisation and a central cystic area on contrast-enhanced
CT suggested that the upper mass could be a phaeochromocytoma
[6β-131I] iodomethyl-19 nor-cholesterol (NP-59) scintigraphy,
123I-metaiodobenzylguanidine (MIBG).
An adrenocortical
adenoma causing
Cushing's
syndrome and a
pheochromocytoma
had actually
developed in the
same adrenal
gland.
Maternal deaths averted by contraceptive use: an analysis of 172 countries
Family planning is one of the four pillars of the Safe Motherhood Initiative to reduce maternal
death in developing countries. We aimed to estimate the effect of contraceptive use on
maternal mortality and the expected reduction in maternal mortality if the unmet need for
contraception were met, at country, regional, and world levels. We extracted relevant data
from the Maternal Mortality Estimation Inter-Agency Group (MMEIG) database, the UN World
Contraceptive Use 2010 database, and the UN World Population Prospects 2010 database,
and applied a counterfactual modelling approach (model I), replicating the MMEIG (WHO)
maternal mortality estimation method, to estimate maternal deaths averted by contraceptive
use in 172 countries. We used a second model (model II) to make the same estimate for 167
countries and to estimate the effect of satisfying unmet need for contraception. We did
sensitivity analyses and compared agreement between the models.
Contraceptive prevalence rate and
estimated maternal mortality
reduction
Expected reduction in maternal deaths if
unmet needs for contraception are
fulfilled
Simulation results, presented at the
aggregated level, of number of maternal
deaths per year if anticipated
contraceptive demand is met (red bars)
or not met (blue bars). Countries
included in each regional category are
listed in table 2. CIS=Commonwealth of
Independent States. *Transitional
countries of southeastern Europe.
Our results suggest that family planning
probably prevents about 272 000
maternal deaths worldwide per year
Equity in financing and use of health care in Ghana, South Africa, and
Tanzania: implications for paths to universal coverage
Universal coverage of health care is now receiving substantial worldwide and national attention,
but debate continues on the best mix of financing mechanisms, especially to protect people
outside the formal employment sector. Crucial issues are the equity implications of different
financing mechanisms, and patterns of service use. We report a whole-system analysis—
integrating both public and private sectors—of the equity of health-system financing and service
use in Ghana, South Africa, and Tanzania. We used primary and secondary data to calculate the
progressivity of each health-care financing mechanism, catastrophic spending on health care,
and the distribution of health-care benefits. We collected qualitative data to inform interpretation.
Kakwani Indices for financing sources in Ghana,
South Africa, and Tanzania
A negative index shows a regressive financing
mechanism and a positive index a progressive
mechanism. *Contributions by the informal sector in
Ghana (although legislation requires all Ghanaians to
join the national health insurance scheme,
membership is effectively voluntary for people outside
the formal sector); contributions to private healthinsurance schemes in South Africa; and contributions
to the Community Health Fund and related schemes
in Tanzania. †Mandatory insurance in Ghana includes
only the contributions by formal-sector employees.
‡General taxes refer to the combination of direct and
indirect taxes.
Overall health-service benefits favoured
the rich in all three countries, with services
being most pro-rich in South Africa and
only marginally so in Tanzania.
The overall distribution of service benefits
in all three countries favoured richer
people, although the burden of illness was
greater for lower-income groups. Access
to needed, appropriate services was the
biggest challenge to universal coverage in
all three countries.
Reconstructive surgery after female genital mutilation: a prospective cohort
study
Women who have undergone female genital mutilation rarely have access to the reconstructive
surgery that is now available. Our objective was to assess the immediate and long-term outcomes
of this surgery. Between 1998 and 2009, we included consecutive patients with female genital
mutilation aged 18 years or older who had consulted a urologist at Poissy-St Germain Hospital,
France. We used the WHO classification to prospectively include patients with type II or type III
mutilation. The skin covering the stump was resected to reveal the clitoris. The suspensory
ligament was then sectioned to mobilise the stump, the scar tissue was removed from the exposed
portion and the glans was brought into a normal position. All patients answered a questionnaire at
entry about their characteristics, expectations, and preoperative clitoris pleasure and pain,
measured on a 5-point scale. Those patients who returned at 1 year for follow-up were questioned
about clitoris pain and functionality. We compared data from the 1-year group with the total group
of patients who had surgery.
Every year, an estimated 3 million girls are at risk of undergoing the procedure. Female genital
mutilation is widespread in Africa, but also occurs in immigrant communities in Europe and North
America. It has medical, psychological, and psychosexual consequences, which have been
described in detail. Nor should one forget the unacceptably high number of young girls who die as
a result of life-threatening infections such as tetanus or haemorrhage; in areas of Sudan where
antibiotics are not available, a third of the girls undergoing female genital mutilation are estimated
to die from infection.
Excision, scarring, and
reconstruction of female
genital mutilation
(A) Scheme representing the
anatomy of a non-mutilated
clitoris. Effect of further
cutting of clitoral glans is
represented by a red line. (B)
Example of a non-mutilated
clitoris. (C) Fixed clitoris after
scarring: the surgery consists
of freeing the clitoris from the
bone adherence that
immobilises it and thwarts its
dynamic physiology. (D)
Example of type 2 mutilation
with pseudoinfibulation. (E)
Scheme representing the
outcome after reconstructive
surgery. (F) Example of
aesthetic outcome at 1 year
after reconstructive surgery,
with an apparent functional
clitoris, and aesthetic labia
minora.
We have shown that reconstructive surgery after female genital mutilation reduces
local pain and restores clitoral pleasure. These unmet needs are inadequately
assessed, because sequelae from female genital mutilation are not easily disclosed
by women. Our work was not publicised, however, in 2004 the issue gained publicity
(newspapers, television) after the decision of the French health-care system to
reimburse the surgical procedure, which might have affected the the increase in
recruitment in 2004. The proportion of patients with female genital mutilation who had
never had clitoral pleasure rose with year of attendance.
A single surgeon (PF) did all 2938 procedures using the same technique in the same
hospital. All consecutive patients were included, and few data of those patients
followed up were missing.
CT sections at L3 level of the two subjects
51-year-old man (left) and 53-year-old woman (right). The left image also shows calcifications of
the abdominal aorta and nephrosclerosis. Same age, same BMI (30)
Global population trends and policy options
Rapid population growth is a threat to wellbeing in the poorest countries, whereas very low
fertility increasingly threatens the future welfare of many developed countries. The mapping
of global trends in population growth from 2005—10 shows four distinct patterns. Most of
the poorest countries, especially in sub-Saharan Africa, are characterised by rapid growth
of more than 2% per year. Moderate annual growth of 1—2% is concentrated in large
countries, such as India and Indonesia, and across north Africa and western Latin America.
Whereas most advanced-economy countries and large middle-income countries, such as
China and Brazil, are characterised by low or no growth (0—1% per year), most of eastern
Europe, Japan, and a few western European countries are characterised by population
decline.
Percentage of married women with unmet need for contraception by region, 1990–95, 2000–05,
and 2009. Data from UN world contraceptive use, 2010.9 LAC=Latin America and Caribbean.
N=North. S=southern. SSA=sub-Saharan Africa.
An uncommon cause of pleural effusions in a dialysis patient
A 42-year-old woman presented in October, 2011, describing dyspnoea, a non-productive cough,
left-sided pleuritic chest discomfort, and 10 kg weight loss over 2 months. She had been receiving
maintenance haemodialysis via a right brachiocephalic arteriovenous fistula. 3 weeks into her
hospital stay, the left pleural effusion re-accumulated with a new right effusion. At 6 weeks there
was a marked deterioration with the patient developing worsening tachycardia and MR alongside a
gallop rhythm. Blood pressure was maintained. Echocardiography now showed a dilated left
ventricle with severe systolic dysfunction, moderate MR, and new pulmonary hypertension
(pulmonary arterial pressure about 48 mm Hg). We noted that the patient's fistula seemed large for
her body size, with a blood flow of 2·7 L/min on Doppler ultrasonography. The echocardiographic
estimate of cardiac output was 6·8 L/min.
An echocardiogram done 10 days after
the fistula ligation showed mild leftventricular dilatation with persistent
systolic impairment but a normal sized
left atrium and only mild MR.
Pulmonary artery pressure was normal.
Cardiac output was calculated to be 5·1
L/min. When last reviewed in June,
2012, the patient was clinically well.
Doppler assessment of fistula flow (Qa) relative to echocardiographic assessment of cardiac output
(CO) can support the diagnosis (Qa/CO >30—35%, or Qa >1 L/min or >25% of CO). Without
intervention, mortality is high. Reduction of fistula size by banding or ligation can improve cardiac
function and reduce morbidity and mortality.