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Resistance to single cytokine blockade, namely anti-tumor necrosis factor (TNF) therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines interferon (IFN)-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet.Using an adaptive immune-mediated colitis model, human colonic lymphocytes from patients with IBD and multiple large clinical datasets, we investigate the effect of cyclin-dependent kinase 9 (CDK9) inhibitors on cytokine production and gene expression in colonic CD4Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4Collectively, our findings reveal CDK9 as a potential target for anti-TNF-resistant IBD, which has the potential for rapid translation to the clinic.

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P=0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P=0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. Fil: Oladapo, Olufemi T.. Organizacion Mundial de la Salud; Argentina Fil: Vogel, Joshua P.. Organizacion Mundial de la Salud; Argentina Fil: Piaggio, Gilda. Organizacion Mundial de la Salud; Argentina Fil: Nguyen, My-Huong. Organizacion Mundial de la Salud; Argentina Fil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina Fil: Metin Gülmezoglu, A.. Organizacion Mundial de la Salud; Argentina Fil: Bahl, Rajiv. Organizacion Mundial de la Salud; Argentina Fil: Rao, Suman P.N.. Organizacion Mundial de la Salud; Argentina Fil: de Costa, Ayesha. Organizacion Mundial de la Salud; Argentina Fil: Gupta, Shuchita. Organizacion Mundial de la Salud; Argentina Fil: Shahidullah, Mohammod. No especifíca; Fil: Chowdhury, Saleha B.. No especifíca; Fil: Ara, Gulshan. No especifíca; Fil: Akter, Shaheen. No especifíca; Fil: Akhter, Nasreen. No especifíca; Fil: Dey, Probhat R.. No especifíca; Fil: Abdus Sabur, M.. No especifíca; Fil: Azad, Mohammad T.. No especifíca; Fil: Choudhury, Shahana F.. No especifíca; Fil: Matin, M.A.. No especifíca; Fil: Goudar, Shivaprasad S.. No especifíca; Fil: Dhaded, Sangappa M.. No especifíca; Fil: Metgud, Mrityunjay C.. No especifíca; Fil: Pujar, Yeshita V.. No especifíca; Fil: Somannavar, Manjunath S.. No especifíca; Fil: Vernekar, Sunil S.. No especifíca; Fil: Herekar, Veena R.. No especifíca; Fil: Bidri, Shailaja R.. No especifíca; Fil: Mathapati, Sangamesh S.. No especifíca; Fil: Patil, Preeti G.. No especifíca; Fil: Patil, Mallanagouda M.. No especifíca; Fil: Gudadinni, Muttappa R.. No especifíca; Fil: Bijapure, Hidaytullah R.. No especifíca; Fil: Mallapur, Ashalata A.. No especifíca; Fil: Katageri, Geetanjali M.. No especifíca; Fil: Chikkamath, Sumangala B.. No especifíca; Fil: Yelamali, Bhuvaneshwari C.. No especifíca; Fil: Pol, Ramesh R.. No especifíca; Fil: Misra, Sujata S.. No especifíca; Fil: Das, Leena. No especifíca

ObjectivesInforming research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.DesignIn the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.SettingUK stroke services.Participants3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.ResultsOf those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.ConclusionIt is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration numberISRCTN83290762; Post-results.

Innate lymphoid cells (ILCs) are emerging as important effectors of innate immunity and play a critical role in maintaining intestinal immune homeostasis. They are tissue-residing immune cells that can be subdivided based on master transcription factor and cytokine expression, bearing striking resemblance to their CD4

Leydig cell tumour (LCT) of the testis is a rare histological subtype of stromal tumours, accounting for 1 to 3% of testicular neoplasms. The natural history of LCT is poorly understood. The aim of this study was to assess the incidence and natural history of Leydig cell tumours (LCT) of the testes. A search of the National Cancer Registry of Ireland database was performed regarding Leydig cell testicular tumours. Recurrence free survival (RFS) and disease-specific survival (DSS) were analysed. Between 1994 and 2013, 2755 new cases of testicular cancer were diagnosed in Ireland. Of these, 22 (0.79%) were Leydig cell tumours. Nineteen were invasive (stage T1) and three were in situ (stage Tis). One patient developed a local recurrence following an organ preserving procedure and underwent a completion orchidectomy 107 days after initial diagnosis. No further treatment was required. There have been no disease-specific deaths. The 1-, 3- and 5-year overall survival (OS) rates were 95.5, 88.2 and 73.3%, respectively. The 5-year disease-specific survival (DSS) was 100% and the 5-year recurrence free survival (RFS) was 93.3%. From the National Cancer Registry, LCT has been shown to be a rare subtype of testicular tumour. Due to the relatively favourable natural history, it may be possible to tailor less aggressive surveillance regimens in these patients.

Hyposplenism is associated with autoimmune diseases, inflammatory bowel disease, severe celiac disease, autoimmune thyroiditis, untreated HIV infection and chronic graft-versus-host disease. The aim of this study was to review the existing data on hyposplenism associated with celiac disease and Hashimoto's autoimmune thyroiditis. Our research was based on a clinical case concerning a 41-year-old female who presented with asthenia, fatigue, dyspepsia and chronic diarrhea. The medical history revealed autoimmune Hashimoto's thyroiditis, type 2 diabetes, fatty liver disease, chronic gastritis and thrombocytosis. Multiple investigations showed hyposplenism and complex autoimmune dysfunction with positive serum markers for celiac disease and type 1 autoimmune hepatitis along with minor symptomatology. The intestinal symptomatology of celiac disease is often hid by hypothyroidism-associated autoimmune thyroiditis. Asymptomatic or minimally symptomatic celiac disease associated with Hashimoto's autoimmune thyroiditis is diagnosed by biomarkers. Hyposplenism in celiac disease can occur regardless of the disease stage, latent or symptomatic.

The prognosis of liver cirrhosis depends on the presence of its major complications as well as on other factors such as hypersplenism with thrombocytopenia. Partial splenic embolization is an effective interventional procedure performed in liver cirrhosis complicated with portal hypertension to improve the low platelet count. This technique represents an efficient alternative to splenectomy, which has major drawbacks and is associated with a high morbidity. We report a series of patients with liver cirrhosis and portal hypertension who presented with severe thrombocytopenia and were treated with partial splenic embolization eventually having a favourable outcome.

The upper digestive hemorrhage is one of the main causes of mortality from liver cirrhosis (CH). The measurement of the hepatic venous pressure gradient (HVPG) by angiographic way can be used for the determination of the risk of hemorrhage. The aim of this study is to verify the influence of the HVPG measurement upon the survival in patients with CH and upper digestive hemorrhage. A retrospective pilot study on 33 patients with upper digestive hemorrhage divided into two groups according to the therapeutic attitude followed, was carried out. One group was classically treated, with variceal band ligation, non-elective beta-blockers and in emergency Octreotide. The other group was treated depending on the value of HVPG. From the moment of the first episode of digestive hemorrhage, the survival period was in average of 8.1 months for the patients with viral etiology and for those with alcoholic etiology it was of 19.7 months. In patients treated after HVPG measurement, the average survival period was of 34.2 months and in patients “classically” treated, the average survival period was of 15.5 months (significant difference). In conclusion, the measurement of HVPG allowed the selection of a high-risk group of patients. This permitted the making of a therapeutical decision with a significant prolongation of life in these patients.

Assisted reproductive technology has helped many childless couples. It has also raised questions about how appropriate the technology might be in different situations. How we understand parenthood is crucial in taking a stand on such scientific intervention. It is suggested that physicians should decide on offering artificial insemination, surrogacy and in-vitro fertilisation only after considering if the child will have good parents and if there will be legal complications from the use of the technology.

This work was designed with the purpose of determining whether the presence of allelic imbalances (AI) such as microsatellite instability (MSI) and loss of heterozygosity (LOH) in chromosomes 2, 11, 13, and 17 in primary breast cancer could be used as prognostic indicators of patient survival. The DNA from breast cancers removed from 29 patients who were followed-up for up to five years was analyzed for MSI and LOH using a panel of 24 markers located at chromosome 2 (TPO, D2S131, D2S144, D2S171, D2S177, D2S119, D2S123, D2S147 and D2S136), chromosome 11 (C-RAS, Int-2, D11S940, D11S912), chromosome 13 (D13S289, D13S260, D13S267, D13S218, D13S263, D13S155, and D13S162), and chromosome 17 (D17S513, TP53, D17S855, and D17S785). The frequency of AI in the markers studied ranged from 30-55%, being highest for D11S912, D2S171, TP53 and D17S855. Univariate analysis showed association between overall survival rate and AI in 9 out of the 24 markers tested. Five of them were located at the area of the mismatch repair gene (MMR)-2 gene, two at 11p, one at 13q and one at 17p. Using multivariate analysis, it was observed that only pathological and clinical stage (defined as stage II or not) and AI at D2S171, D11S912, or D17STP53 generated significant predictive models for survival.

Paraplegia caused by intrathecal chemotherapy has no known pathognomonic features and is a diagnosis of exclusion.The authors reported the clinical and neuroimaging findings in one patient with this syndrome.The patient had severe paraplegia with urinary retention and impaired pain and touch sensation below T-10 with sparing of proprioception and vibration sense. Magnetic resonance imaging (MRI) scan showed diminished intensity throughout the central cervical spinal cord. Post-gadopentetate dimeglumine enhancement was scattered throughout the cervical spinal cord and in two areas of the dorsal spinal cord. Axial views of the cervical spinal cord showed that this enhancement was limited to the lateral columns.The MRI in myelopathy due to intrathecal chemotherapy may show a unique pattern of postgadopentetate dimeglumine enhancement limited to the lateral columns of the spinal cord. However, two recently encountered patients with the same syndrome did not show similar changes.

Louse-borne relapsing fever seems to have become endemic in the southern Sudan. The epidemic history of the disease in the Sudan is reviewed. We have studied 363 Sudanese patients involved in an outbreak of louse-borne relapsing fever in Khartoum (Sudan) between January and June 1974. 318 of the 363 patients were new immigrants from the soughern Sudan to Khartoum. The clinical presentation varied. The common clinical fetures of the disease were: fever (94%), headache (85%), hepatosplenomegaly (74%), body and joint pains (66%), abdominal pain and tenderness (63%), jaundice (46%) and epistaxis (40%). Thrombocytopenia was common. Biochemical evidence of hepatocellular and renal damage was present in most patients. The mortality rate was 5-5% with treatment. Post-mortem examination was performed on six cases. The organs predominantly involved were the liver, spleen, brain and lungs. The common causes of death were severe hepatic damage, lobar pneumonia, subarachnoid haemorrhage and splenic rupture.

The unique combination of a late complication of Schistosoma mansoni infection in situs invertus is reported. The improvement in both the haematological and biochemical indices of the patient after splenectomy is discussed. An association between chronic salmonellosis and schistosomiasis is demonstrated; the experience of the author and other workers with this syndrome is discussed.

In a study of cutaneous leishmaniasis (CL) caused by Leishmania major in Saudi Arabia, 10% of the patients were found to have subcutaneous nodules (SCN). The SCNs were usually inconspicuous, painless, and proximal to the primary skin lesions; when multiple, they showed a "sporotrichoid" configuration or appeared as "beaded cords." Their number ranged from 1-16 (average 3 25 +/- 2.50; mean +/- 1 SD). In some patients, the SCNs seemed to be triggered by antileishmanial treatment. The clinical picture and pathologic findings suggest that SCNs in patients with CL represent lymphatic dissemination, a phenomenon not widely recognized.

In a study of zoonotic cutaneous leishmaniasis (CL) due to leishmania major in an endemic focus in Saudi Arabia, lymph node enlargement was observed in 66 of 643 patients (10.26%). The epitrochlear lymph nodes were most commonly involved (68%), but cervical (11%), axillary (15%), and inguinal (18%) lymph nodes were also involved. In eight patients (12%), two lymph node areas were involved. The affected lymph nodes were typically solitary, firm, mobile, nontender, only moderately enlarged, and appeared to persist beyond the clinical healing of the associated skin lesions. The results of pathologic and immunopathologic studies carried out on eight lymph nodes obtained from this group of patients supported the leishmanial etiology. Although amastigotes were only demonstrated in two lymph nodes, the leishmanial antigen was found in all eight specimens. The lymph node involvement is another manifestation of dissemination in infection with a dermotropic leishmania. It appears that in some cases, instead of the parasite, it may be the leishmanial antigen that disseminates and produces lymphadenitis.

The effect of metrifonate (Bilarcil Bayer) on Schistosoma haematobium and S. mansoni infections was studied in 174 patients near Khartoum. A high cure rate was obtained in S. haematobium infections, but anthelmintic efficacy was minimal in patients passing S. mansoni eggs in their stools. There was, however, a marked reduction of egg output in patients passing S. mansoni eggs in urine. This suggests that the site of infection in man, rather than the species of parasite, renders the parasite more susceptible to metrifonate. The significance of this and the possibility that these results further clarify the mode of action of metrifonate are discussed.

Cutaneous leishmaniasis (oriental sore) is characterized by slowly evolving inflammatory lesion(s) that are nodular, noduloulcerative, or ulcerative and that heal spontaneously with scar(s) in 3 to 12 months. In the course of a comprehensive study of cutaneous leishmaniasis due to Leishmania major in an endemic focus in Saudi Arabia, seven clinical features of diagnostic value were identified and their approximate frequency in a selected group of 475 patients was determined. These features were: exposed site location, 84%; pairing or clustering of lesions, 61.72%; skin crease orientation, 35.37%; volcanic nodules, 30.32%; satellite papules, 19.37%; subcutaneous nodules, 11.37%; and "iceberg" nodules, 4.63%. This information should serve the process of clinical diagnosis and may be relied upon when the procedures for parasite detection are negative or unavailable.

Extensive studies of the use of the ELISA test for the detection of antibodies in Schistosoma mansoni infections are described. A method has been evolved for the determination of the optimum value for the reference serum endpoint. In chimpanzees infected with S. mansoni a crude egg antigen detected antibodies earlier in the infection than did a worm antigen and was generally more reactive. The ELISA test, using the egg antigen, has been applied to sera from populations infected with S. mansoni, with other human schistosomes, or with helminth infections other than schistosomiasis. The ELISA test was as sensitive as the IFAT and CFT, but more specific. However, many cross-reactions occurred in infections with other human (and with animal) schistosomes, although to a lesser extent with other helminths. In surveys in the Sudan the use of blood collected on absorbent paper was only slightly less sensitive for the detection of antibodies than sera, and this technique showed that the prevalence of infection was higher than that measured by stool examination alone. Possible future developments are discussed with a view to improving sensitivity and specificity both for clinical and epidemiological work.

Oral and intravenous glucose tolerance tests were carried out on patients with Schistosoma mansoni infection with hepatic enlargement. Impaired glucose tolerance was discovered by the oral and intravenous tests. The impaired glucose tolerance was not related to the severity of liver damage as revealed by liver function tests. Abnormal growth hormone secretion is reported. Insulin resistance and pancreatic involvement in hepatic schistosomiasis are discussed.

The efficacy and acceptability of oral oxamniquine were assessed in Sudanese patients infected with Schistosoma mansoni. Cure rates, determined by the absence of viable eggs in the stools six months after treatment, were 94.9% in patients treated with a total of 60 mg/kg, 78.8% in patients treated with 40 mg/kg, and 68.9% in patients treated with 30 mg/kg. All treatment regimens considerably reduced the egg count in those patients not cured. The drug was well tolerated and the side effects were minimal and transient, the most common being dizziness. Most of the patients noticed a reddish discoloration of their urine, which was probably caused by a metabolite of the drug. In patients who received 60 mg/kg oxamniquine there were transient rises in eosinophil counts and in serum alanine aminotransferase concentrations. Though 60 mg/kg was by far the most effective dose in terms of cure rate, egg counts were significantly reduced on all three doses. The lower doses could therefore be useful in a low-cost control programme in reducing transmission of S mansoni infection.

A cross sectional study of schistosomiasis in migrant labourers in the Sudan Gezira is described. The people examined were of two ethnic groups: (i) those of local Arabic origin and (ii) those from Western Sudan, West Africa or west of longitude 27 °E. These two migrant groups were examined in one area treated with molluscicide and in another that was not. Almost all the schistosome infections were with Schistosoma mansoni , with a prevalence of 57% over-all and up to 89% in particular groups. The prevalence was lower in the treated than in the untreated area, and slightly lower in the Arab nomads than in the others, except that it was markedly lower in females from the West in the treated area. These results are consistent with the known water-contact habits of the two migrant groups. An association was observed between infection and liver and spleen enlargement, but not between infection and other symptoms. The potential importance of migrants in transmitting the infection is discussed.

In this paper we report two unusual cases of leprosy, both presenting with lymphadenopathy as the initial manifestation of the disease. Lymphadenopathy was the dominant presenting complaint of the first patient in whom skin lesions were absent. A diagnosis of lepromatous leprosy was made only after a lymph node biopsy. Following this diagnosis neural involvement was evident. In the second patient the lymphadenopathy was associated with polyarthritis leading to a false clinical diagnosis of Still's disease. This unusual presentation in both cases led to a delay in the final diagnosis which was based on histopathological examination of lymph nodes. The clinical and histopathological features of both patients are discussed. Superficial nerves should be palpated in all patients presenting with lymphadenopathy in endemic areas.

A review of 288 skin biopsy specimens from cutaneous leishmaniasis lesions caused by Leishmania major showed assorted nerve changes in 14 biopsy specimens (5%). Ten patients had perineural inflammatory cell infiltrate consisting of either lymphocytes or a mixture of lymphocytes, plasma cells, and macrophages. Four patients had inflammatory cell invasion of the nerves (neuritis), and in one of them the inflammation was granulomatous and associated with nerve destruction. Amastigotes were seen inside the nerves in two patients. Sensory testing of 50 consecutive patients with cutaneous leishmaniasis identified two patients with diminished sensations over the lesions.

Morphometrical analysis of different types of liver cells was performed in cases of chronic active hepatitis (CAH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). The area and a form factor (form AR) of nuclei and cytoplasms were determined, and the nucleo-cytoplasmic ratio (N/C) was calculated in normal hepatocytes, HBsAg-positive cells, large dysplastic cells, cancer cells and in a liver cell population identifiable as "small dysplastic cells" (small cells). The nucleo-cytoplasmic ratio of the small cells and of the neoplastic cells was roughly the same and the highest. Large dysplastic cells showed a small nucleo-cytoplasmic ratio, almost comparable with that of normal hepatocytes and similar to that of HBsAg-positive cells. Since cellular precursors of liver cancer are expected to have a nucleo-cytoplasmic ratio similar to that of neoplastic cells, our morphometrical evaluation indicates small cells as the true precancerous cells; liver cell dysplasia (large dysplastic cells), as described by Anthony et al., should not be considered as a true preneoplastic change.

Patients with schistosomiasis mansoni and schistosomiasis haematobium from the Gezira area of the Sudan were investigated for the simultaneous presence of Schistosoma mansoni and S. haematobium eggs in urine. Before treatment, 28 or 34 mixed-infection patients constantly excreted eggs of S. mansoni in the urine; however, the concentration was only 1.7% that of S. haematobium eggs. Patients were given two doses of metrifonate (10 mg/kg body weight) 2 weeks apart in order to compare the effect of the organophosphorous compound on the two parasite species. Each dose of metrifonate was followed by a significant decrease in egg output in urine (P less than 0.01). The egg reduction was similar for both parasite species, and was almost 99% after the second treatment. Before treatment was started, a positive correlation existed between the numbers of S. haematobium and S. mansoni eggs excreted in urine (r = 0.75, P less than 0.001), and this correlation did not change after the first or the second dose of metrifonate. After treatment, in 6 of 37 patients S. haematobium eggs and in 8 of 28 patients S. mansoni eggs were not, or were only slightly, reduced. When chemotherapeutic failure of metrifonate against S. haematobium or S. mansoni occurred, it was quantitatively similar for both parasite species.

We describe the cases of 2 adult patients who developed respiratory arrest and were found to have Arnold-Chiari malformation on magnetic resonance imaging. Following posterior fossa decompression both patients improved, though one of them subsequently died during sleep. Imaging of the craniocervical junction should be part of the workup of patients with unexplained apneic episodes.