Comorbidities, mortality and survival in patients with pyoderma gangrenosum: a Danish nationwide registry-nested case-control study.

BACKGROUND: Pyoderma gangrenosum (PG) is an ulcerative skin disease associated with comorbidities and increased mortality; however, the literature on this topic is scarce. OBJECTIVES: To investigate the mortality, prevalence and risk of comorbidities in patients with PG. METHODS: This nationwide registry nested case-control study included all inpatients and outpatients diagnosed with PG in tertiary dermatology centres in Denmark between 1 January 1994 and 31 December 2016. Each case was matched on date of birth and sex with 10 unique controls. The Danish National Patient Registry was used to identify all patients and to gather information on comorbidity. Information on age, sex, vital status and emigration was obtained from the Danish Civil Registration System. The outcomes were 19 different comorbidities and all-cause mortality. Prevalence was assessed from odds ratios (ORs) for specific comorbidities at the time of PG diagnosis. The risk of developing specific comorbidities and death was assessed using hazard ratios (HRs) obtained using the Cox proportional-hazards model. RESULTS: A total of 1604 patients with PG were matched with 16 039 controls. Some associations were known, e.g. inflammatory bowel disease [OR 19·15 (15·27-24·02), HR 6·51 (4·24-10·01)], while others have not been described previously, e.g. osteoporosis [OR 1·57 (1·22-2·02), HR 2·59 (2·08-3·22)]. Mortality was significantly increased among patients with PG [HR 2·79 (2·57-3·03)]. CONCLUSIONS: Patients with PG have increased mortality and an increased prevalence and risk of both previously reported and novel comorbidities that may have severe consequences if left undiagnosed. Our findings are mainly related to moderate and severe PG.

Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV).

BACKGROUND: Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. OBJECTIVES: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. RESULTS: The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.

Alemtuzumab is effective against severe chronic lymphocytic leukaemia-associated paraneoplastic pemphigus.

Alemtuzumab (ALZ) is a monoclonal antibody used in the treatment of a variety of lymphoproliferative diseases, primarily chronic lymphocytic leukaemia (CLL). Paraneoplastic pemphigus (PNP) is a severe mucocutaneous disease, which can occur in association with B-cell malignancies. A correct diagnosis of PNP relies on distinct clinical and histopathological features, and the demonstration, by direct immunofluorescence, of intercellular and basement membrane IgG deposits in the affected tissue. PNP is often refractory to immunosuppressive drugs and frequently has a fatal outcome. We report three cases where sustained remissions of both PNP and CLL were induced by ALZ. In one of these cases, ALZ was able to reinduce a sustained remission of PNP at the reappearance of the disorder years after the primary treatment. In all cases, the PNP diagnosis was confirmed by immunofluorescence. In conclusion, ALZ should be considered as a treatment option in severe CLL-associated PNP. Patients should be carefully selected and receive appropriate infectious prophylaxis before, during and after ALZ treatment, due to the risk of opportunistic infections secondary to combined disease- and drug-induced immunosuppression.

Influence of Resistance Training on Neuromuscular Function and Physical Capacity in ALS Patients.

OBJECTIVES: The present study aimed to explore the effect of resistance training in patients with amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motor neuron loss and muscle weakness. MATERIALS AND METHODS: Following a 12-week "lead-in" control period, a population of ALS patients from Funen, Denmark, completed a 12-week resistance training program consisting of 2-3 sessions/week. Neuromuscular function (strength and power) and voluntary muscle activation (superimposed twitch technique) were evaluated before and after both control and training periods. Physical capacity tests (chair rise and timed up and go), the revised ALS functional rating scale (ALSFRS-R) scores, and muscle cross sectional area (histology) were also assessed. RESULTS: Of twelve ALS patients assessed for eligibility, six were included and five completed the study. Training did not significantly affect the ALSFRS-R score, and loss of neuromuscular function (strength and power) increased following the training period. However, an improved functionality (chair rise) and an increase in greatly hypertrophied type II fibres combined with an increase in atrophied fibres following the training period compared to the control period were observed. CONCLUSION: In this small study, the present form of resistance training was unable to attenuate progressive loss of neuromuscular function in ALS, despite some changes in physical capacity and morphology.

Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis.

Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing skeletal muscle biopsies from ALS patients collected before and after a 12-week period of normal daily activities and compare these with healthy age-matched control tissue. We do this by evaluating mRNA and protein (immunohistochemical) markers of regeneration, neurodegeneration, myogenesis, cell cycle regulation, and inflammation. Our results show morphological changes indicative of active denervation and reinnervation and an increase in small atrophic fibres. We demonstrate differences between ALS and controls in pathways controlling skeletal muscle homeostasis, cytoskeletal and regenerative markers, neurodegenerative factors, myogenic factors, cell cycle determinants, and inflammatory markers. Our results on Pax7 and MyoD protein expression suggest that proliferation and differentiation of skeletal muscle stem cells are affected in ALS patients, and the myogenic processes cannot overcome the denervation-induced wasting.

Intracranial baroreflex yielding an early cushing response in human.

The Cushing response is a pre-terminal sympatho-adrenal systemic response to very high ICP. Animal studies have demonstrated that a moderate rise of ICP yields a reversible pressure-mediated systemic response. Infusion studies are routine procedures to investigate, by infusing CSF space with saline, the cerebrospinal fluid (CSF) biophysics in patients suspected of hydrocephalus. Our study aims at assessing systemic and cerebral haemodynamic changes during moderate rise of ICP in human. Infusion studies were performed in 34 patients. This is a routine test perform in patients presenting with symptoms of NPH during their pre-shunting assessment. Arterial blood pressure (ABP) and cerebral blood flow velocity (FV) were non-invasively monitored with photoplethysmography and transcranial Doppler. The rise in ICP (8.2 +/- 5.1 mmHg to 25 +/- 8.3 mmHg) was followed by a significant rise in ABP (106.6 +/- 29.7 mmHg to 115.2 +/- 30.1 mmHg), drop in CPP (98.3 +/- 29 mmHg to 90.2 +/- 30.7 mmHg) and decrease in FV (55.6 +/- 17 cm/s to 51.1 +/- 16.3 cm/s). Increasing ICP did not alter heart rate (70.4 +/- 10.4/min to 70.3 +/- 9.1/min) but augmented the heart rate variance (0.046 +/- 0.058 to 0.067 +/- 0.075/min). In a population suspected of hydrocephalus, our study demonstrated that a moderate rise of ICP yields a reversible pressure-mediated systemic response, demonstrating an early Cushing response in human and a putative intracranial baroreflex.

Treatment of active distal ulcerative colitis with immunoglobulin G enemas.

Seven patients with active distal ulcerative colitis were treated with IgG enemas given as a daily bedtime retention enema for two weeks. Evaluation of effect was assessed by means of sigmoidoscopy with biopsy, measuring acute phase reactants in peripheral blood, and measuring the faecal protein loss. Clinical signs of active disease were registered by the patients on a diary chart. Five patients completed the treatment period, two patients were withdrawn after 7 and 10 days due to deterioration of disease. Four patients did not register any effect, whereas one patient improved clinically. In conclusion, rectally administered IgG did not exert any effect on rectal ulcerative colitis in our study.

Frontal brain and leptomeningeal biopsy specimens correlated with cerebrospinal fluid outflow resistance and B-wave activity in patients suspected of normal-pressure hydrocephalus.

OBJECTIVE: Normal-pressure hydrocephalus (NPH) is a potentially treatable syndrome with abnormal cerebrospinal fluid dynamics. Meningeal fibrosis and/or obliteration of the subarachnoid space has been suggested as the pathoanatomic basis. The purpose of the present study was to investigate whether meningeal fibrosis causes increased resistance to cerebrospinal fluid outflow (R(out)) and/or increased B-wave activity and whether pathological changes in the brain parenchyma after brain compliance, causing increased B-wave activity. METHODS: The study involved a group of 38 consecutively studied patients with clinical and radiological evidence of idiopathic NPH, for whom a frontal brain biopsy was obtained. For 29 patients, hydrodynamic criteria of NPH were fulfilled and a ventriculoperitoneal shunt was performed. RESULTS: Meningeal fibrosis was found in 12 of 25 biopsies containing arachnoid tissue, but no correlation with R(out) or B-waves was found. Pathological parenchymal changes, most often Alzheimer's disease (10 cases) or vascular changes (10 cases), were found in 21 biopsies, but no correlation with B-waves or R(out) was found. CONCLUSION: The results suggest that leptomeningeal fibrosis is not the only pathoanatomic basis of increased R(out) and/or B-wave activity in patients with NPH and that various degenerative changes in the parenchyma may be responsible for the altered cerebrospinal fluid dynamics characteristic of NPH.

Transient impairments in single muscle fibre contractile function after prolonged cycling in elite endurance athletes.

AIM: Prolonged muscle activity impairs whole-muscle performance and function. However, little is known about the effects of prolonged muscle activity on the contractile function of human single muscle fibres. The purpose of this study was to investigate the effects of prolonged exercise and subsequent recovery on the contractile function of single muscle fibres obtained from elite athletes. METHODS: Nine male triathletes (26 ± 1 years, 68 ± 1 mL O2  min(-1) kg(-1) , training volume 16 ± 1 h week(-1) ) performed 4 h of cycling exercise (at 73% of HRmax ) followed by 24 h of recovery. Biopsies from vastus lateralis were obtained before and following 4 h exercise and following 24 h recovery. Measurements comprised maximal Ca(2+) -activated specific force and Ca(2+) sensitivity of slow type I and fast type II single muscle fibres, as well as cycling peak power output. RESULTS: Following cycling exercise, specific force was reduced to a similar extent in slow and fast fibres (-15 and -18%, respectively), while Ca(2+) sensitivity decreased in fast fibres only. Single fibre-specific force was fully restored in both fibre types after 24 h recovery. Cycling peak power output was reduced by 4-9% following cycling exercise and fully restored following recovery. CONCLUSION: This is the first study to demonstrate that prolonged cycling exercise transiently impairs specific force in type I and II fibres and decreases Ca(2+) sensitivity in type II fibres only, specifically in elite endurance athletes. Further, the changes in single fibre-specific force induced by exercise and recovery coincided temporally with changes in cycling peak power output.

Recombinant factor VIIa in joint and muscle bleeding episodes.

Recombinant factor VIIa (rFVIIa) improves haemostasis and eliminates the risk of transmission of blood-borne infection in haemophilia patients with inhibitors, acquired inhibitors to factor VIII or IX or FVII deficiency. rFVIIa has been available on a compassionate use basis since 1988 and has been administered to 111 patients for a total of 494 joint and muscle bleeding episodes. Seventy-nine percent of joint and 65% of muscle bleeding episodes were evaluated by the investigator as having an excellent/effective response. rFVIIa is also an effective treatment for joint and muscle bleeding episodes in patients undergoing immune tolerance regimens and does not affect the inhibitor titre level.

Unusual clinical manifestations of disturbed CSF dynamics in hydrocephalic children.

OBJECTS: Clinical symptoms and signs of increased intracranial pressure (ICP) may be nonspecific and unreliable, or even entirely absent, in hydrocephalic infants and children. Even with a radiological examination, it is often difficult to distinguish between "arrested hydrocephalus" and slowly progressive hydrocephalus requiring treatment. METHODS: We present two cases with unusual and initially misleading clinical manifestations of increased ICP. In both cases, the disturbed cerebrospinal fluid (CSF) dynamics, i.e. raised ICP, were not recognised until demonstrated by a long-term ICP monitoring. In a 5-month-old boy with normal head circumference and normal psychomotor development, the sudden onset of episodes of torticollis and screaming were the only symptoms. No pathology underlying the developing hydrocephalus and the raised ICP could be established, but the boy's condition improved after a shunt operation. In the other case, symptoms and signs consisted primarily in a slowly progressive dilatation of the facial veins with onset at the age of 2-3 years. As the girl also presented a congenital subvalvular aortic stenosis, the venous congestion was initially thought to reflect a vena cava superior syndrome. Further radiological examinations, however, revealed an extensive sinus thrombosis underlying the raised ICP. The girl underwent shunt insertion, and the venous congestion was reduced. CONCLUSIONS: The cases illustrate that though clinical and radiological findings may be very doubtful, or unusual for increased ICP, direct diagnostic long-term ICP monitoring should always be contemplated. Only ICP monitoring can reveal with certainty whether disturbed CSF dynamics are involved, requiring a CSF diverting operation to treat and stabilise the condition.

Indications for shunt insertion or III ventriculostomy in hydrocephalic children, guided by lumbar and intraventricular infusion tests.

The best therapeutic management for infantile hydrocephalus is not always obvious. Traditionally, shunt insertion has been performed when CSF dynamics have been considered abnormal. However, in cases of noncommunicating hydrocephalus endoscopic III ventriculostomy (ETV) has become a well-established treatment modality, but despite clinical and radiological information clinical improvement is not obtained in all cases. A reliable preoperative investigative procedure helping to select hydrocephalic children for ETV, shunt insertion or no operation, is urgently needed. We report three cases of infantile hydrocephalus, in which our operative management was guided by the results of cerebrospinal (CSF) infusion tests. With a lumbar infusion test we assessed the CSF resorption capacity, and thus whether shunting was indicated. Comparing the results with those of an intraventricular infusion test, we assessed the presence of any structural blockage of the CSF circulation between the ventricles and the subarachnoid compartment, which would indicate a possible effect of an ETV. Performance of both a lumbar infusion test and a subsequent intraventricular infusion test in hydrocephalic children seems to provide valuable information for the decision-making on surgery.

Shunting effects in patients with idiopathic normal pressure hydrocephalus; correlation with cerebral and leptomeningeal biopsy findings.

Normal Pressure Hydrocephalus (NPH) is a potentially treatable syndrome with abnormal cerebrospinal fluid dynamics. Meningeal fibrosis and/or obliteration of the subarachnoid space have been suggested as one of the patho-anatomical substrates. However, other types of adult onset dementia, predominantly Alzheimer's disease and Vascular Dementia, may mimic the clinical NPH characteristics. The purpose of the present study was to correlate cerebral parenchymal and leptomeningeal biopsy findings to the clinical outcome after CSF shunting in a prospective group of idiopathic NPH (INPH) patients. The study comprises 27 patients with INPH, diagnosed and shunted according to generally accepted clinical, imaging and hydrodynamic criteria. In all patients a frontal leptomeningeal and brain biopsy was obtained prior to the shunt insertion. Degenerative cerebral changes, most often Alzheimer (6 cases) or vascular changes (7 cases) were described in 14 out of 27 biopsies. Arachnoid fibrosis was found in 9 of the 18 biopsies containing arachnoid tissue. Overall, nine patients (33%) improved, of whom 6 presented Alzheimer or vascular changes in their biopsies. No correlation was found between clinical outcome and the presence or absence of degenerative cerebral changes and/or arachnoid fibrosis. However, a tendency towards higher improvement rates was noted in the subgroups presenting degenerative cerebral changes or arachnoid fibrosis. The results suggest that no constant morphological element exists in the syndrome of INPH. Various aetiologies may be involved in the pathogenesis and possibly in some cases co-existing: Patients may also improve by shunting despite the presence of degenerative cerebral parenchymal changes.

Use of recombinant, activated factor VII in the treatment of congenital factor VII deficiencies.

BACKGROUND AND OBJECTIVES: Factor VII (FVII) deficiency is a rare coagulation disorder, historically treated with prothrombin complex concentrates or plasma-derived FVII concentrates. We treated such patients (n = 17) with a recombinant, activated FVII preparation. MATERIALS AND METHODS: Twenty-seven spontaneous bleeding episodes were treated and 7 major and 13 minor surgical interventions were carried out. The dosages employed ranged from 8.08 to 70.5 Ig/kg body weight. RESULTS: A mean dose between 22 and 26 Ig/kg was sufficient to normalise the prothrombin time. Fifteen haemarthroses were treated with single doses and results were excellent in 13 cases. In 5/6 bleeding episodes of other types, the treatment gave either excellent or at least effective results. Haemostasis was secured in the 7 major and 13 minor surgical interventions. One patient developed antibodies 4-5 weeks after an extremely high dose. Otherwise, there were no side effects and no evidence of a thrombotic tendency. CONCLUSION: This recombinant concentrate is efficacious in FVII-deficient patients. It is safe since any risk of transmission of blood-borne viruses is eliminated.

Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary study.

BACKGROUND & AIMS: Cirrhotic patients with a prolonged prothrombin time (PT) are known to have low levels of factor VII. Because the current modalities to correct this problem are not ideal, recombinant factor VIIa (rFVIIa) may be useful in correcting the prolonged PT observed in the coagulopathy of cirrhosis. The aim of this study was to evaluate the effectiveness of rFVIIa in nonbleeding volunteer patients with the coagulopathy of cirrhosis. METHODS: A preliminary, single-center, dose-escalation trial was performed. Cirrhotic patients with a PT of > 2 seconds above the upper limit of the reference value received an intramuscular injection of vitamin K. Ten patients whose PT did not correct to within 2 seconds above the control of the upper limit of the reference value were given three successive dosages of rFVIIa (5, 20, and 80 micrograms/kg) during a 3-week period. RESULTS: The mean PT transiently corrected to normal in all three dosage groups. No adverse effects were noted. There was no evidence of the induction of disseminated intravascular coagulation. CONCLUSIONS: This preliminary trial shows rFVIIa to be effective in transiently reversing the prolonged PT in a select group of nonbleeding cirrhotic patients. These preliminary observations support conducting a large-scale efficacy trial.

A multidisciplinary memory clinic in a neurological setting: diagnostic evaluation of 400 consecutive patients.

This report describes the operation of a multidisciplinary university hospital memory clinic in a neurological setting, and the diagnostic evaluations in 400 consecutive patients referred for cognitive symptoms and possible dementia during a period of 27 months (1 September 1995-31 December 1997). The mean age of the patients was 63.6 years (range 19-97). On clinical and neuropsychological examination, 46% of the patients fulfilled DSM IV criteria for dementia, 5% had selective amnesia, and 14% had other selective cognitive deficits. The remaining patients had either no significant cognitive deficits (31%) or were not evaluable (4%). A wide range of disorders from the fields of neurology, psychiatry, neurosurgery and internal medicine were identified as the underlying etiologies for the cognitive symptoms. Potentially reversible conditions were observed in 26% of the patients, not including the 11% in whom no specific underlying disease was identified. Concomitant conditions or risk factors with a potential influence on cognitive functions were identified in 61% of the patients. Diagnostic evaluation of patients with mild to moderate cognitive symptoms and possible dementia is an integrated multidisciplinary task, which should focus on the identification of non-progressive and potentially reversible etiologies, co-morbidity, selective cognitive deficits, and rare or atypical neurological conditions, as well as on the early identification of common progressive dementia disorders.